I1-Histone Deacetylase 1

1Histone Deacetylase 1

Dominique Meunier, PhD

and Christian Seiser, PhD

C O NTENT S

S UMMARY

H ISTONE D EACETYLASE 1:A B RIEF H ISTORY

E VOLUTIONARY C ONSERV ATION O

F HDAC1

S TRUCTURAL AND F UNCTIONAL C HARACTERISTICS

OF HDAC1

T RANSCRI P TIONAL R E P RESSION M EDIATED

BY HDAC1

HDAC1 AND THE R EGULATION OF C ELL

C YCLE P ROGRESSION ,P ROLIFERATION ,

AND D IFFERENTIATION

O THER B IOLOGICAL F UNCTIONS OF HDAC1

C ONCLUDING R EMARKS AN

D F UTUR

E D IRECTIONS

A CKNOWLEDGMENTS

R EFERENCES

SUMMARY

HDAC1 was the f i rst h i stone deacetylase i dent i f i ed i n mammals and i s cons i dered the prototype of th i s lar g e fam i ly of enzymes .Transcr i pt i onal repress i on med i ated by HDAC1 plays a cr u c i al role i n the re gu lat i on of a var i ety of b i olo gi cal processes,i ncl u d i n g cell cycle pro g ress i on,prol i ferat i on,and d i fferent i at i on . Interest i n g ly,HDAC1 can also i nfl u ence other cell u lar act i v i t i es,s u ch as DNA repl i cat i on and chro-mosome se g re g at i on,v i a mechan i sms that do not i nvolve transcr i pt i onal repress i on . In add i t i on,HDAC1 i s essent i al for embryon i c development

3

From :Can cer D r ug Dis co v er y and D e v e l o pm e nt

Hist o n e D e a ce tylas e s :T r ans cr ipti o nal Re gulati o n and O th er C e llula r F un c ti o ns

Ed i ted by :E . Verd i n ?H u mana P ress Inc .,Totowa,NJ

4Meunier and Seiser

Acronyms and Abbreviations

BRCA1Breast cancer 1 g ene

CoREST Corepressor of RE1 s i lenc i n g transcr i pt i on factor

EED Embryon i c ectoderm development prote i n

EZH2Enhancer of zeste homolo g 2 (D ro s o phila)

HAT H i stone acetyltransferase

HDA-1H i stone deacetylase 1 (Yeast)

MAD MAX d i mer i zat i on prote i n

MAX MYC-assoc i ated factor X

MBD3Methyl-CpG-b i nd i n g doma i n prote i n 3

MDM2Mo u se do u ble m i n u te 2

M i-2-alpha,Dermatomyos i t i s-spec i f i c a u toant ig en 2 alpha,also called (CHD3)chromodoma i n hel i case DNA-b i nd i n g prote i n 3

M i-2-beta,Dermatomyos i t i s-spec i f i c a u toant ig en 2 beta,also called (CHD4)chromodoma i n hel i case DNA-b i nd i n g prote i n 4

MTA1,MTA2Metastas i s-assoc i ated g ene 1,metastas i s-assoc i ated g ene 2 MYC Myelocytomatos i s onco g ene

NF-Y N u clear transcr i pt i on factor Y

P/CAF p300/CB P-assoc i ated factor

R P D3Red u ced potass iu m dependency 3

SA P18SIN3-assoc i ated polypept i de,18 KDa

SA P30SIN3-assoc i ated polypept i de,30 KDa

SIN3SWI-i ndependent 3

S P1,S P3Spec i f i c prote i n 1,spec i f i c prote i n 3

YY1Y i n g yan g 1

and appears to play a cr i t i cal role i n cell u lar defense a g a i nst v i ral i nfec-t i on.F i nally,i ncreas i n g ev i dence po i nts toward the i mportance of HDAC1 i n t u mor format i on and/or pro g ress i on,and c u m u lat i ve observa-t i ons i nd i cate that the enzyme i s a cr u c i al tar g et for HDAC i nh i b i tors i n cancer therapy.

K ey Wo rds:H i stone deacetylase 1,HDAC1,transcr i pt i onal repress i on, b i olo gi cal f u nct i on,cell cycle re gu lat i on,prol i ferat i on,d i fferent i at i on, repl i cat i on,m i tos i s,development,cancer,chromat i n.

HISTONE DEACETYLASE 1: A BRIEF HISTORY

H i stone deacetylase 1 (HDAC1) was the f i rst prote i n fo u nd to possess h i stone deacetylase act i v i ty i n mammals. Tak i n g advanta g e of the recent

Chapter 1 /HDAC15 d i scovery of trapox i n,a potent i nh i b i tor of HDAC act i v i ty (1,2),Ta u nton and collea gu es (3)i solated HDAC1 from a h u man T-cell l i ne u s i n g a trapox i n-based aff i n i ty matr i x. HDAC1 was s u bseq u ently i dent i f i ed as a g rowth factor-i nd u c i ble enzyme w i th HDAC act i v i ty i n mo u se T-cells (4). Seq u ence analyses revealed that both the h u man and mo u se HDAC1 prote i ns are h ig hly homolo g o u s to the Sa cc ha ro my ce s cere visia e R P D3 prote i n(3–5),a known transcr i pt i onal re gu lator (6). Altho ug h mo u se HDAC1 fa i led to complement the yeast r pd3Δdelet i on(4),extens i ve i nvest ig at i ons s i nce then have clearly demonstrated the cr u c i al role played by HDAC1 i n the transcr i pt i onal repress i on of a var i ety of mammal i an g enes i nvolved i n cell cycle pro g ress i on,prol i ferat i on,d i fferent i at i on, development and cancer.

EVOLUTIONARY CONSERVATION OF HDAC1 The mammal i an HDAC1 prote i n belon g s to an anc i ent fam i ly of enzymes h ig hly conserved thro ug ho u t e u karyot i c and prokaryot i c evol u t i on.

E u karyot i c HDACs have been d i v i ded i nto three classes—I,II and III—based on seq u ence s i m i lar i ty (7,8). HDAC1,to g ether w i th HDAC2,HDAC3,and HDAC8,belon g s to the R P D3-l i ke class I of HDACs. A recent phylo g enet i c analys i s has revealed that class I can be f u rther d i v i ded i nto an HDAC1/HDAC2 and an HDAC3 s u bclass (9). The HDAC1/HDAC2 s u b-class cons i sts of the vertebrate HDAC1 and HDAC2 prote i ns,the s i n g le D ro s o phila m e lan o gast er R P D3 prote i n,and a pa i r of prote i ns i n Ca e n or ha b ditis e l e gans. HDAC1-related prote i ns have also been i dent i f i ed i n several other or g an i sms,i ncl u d i n g ch i cken (10),Xe n o pus la e vis(11), Dani o rer i o(12),A r a b id o psis thaliana(9),ma i ze (13,14),and bacter i a (4).

The ex i stence of an HDAC1/HDAC2 s u bclass w i th i n class I h ig hl ig hts the h ig h de g ree of s i m i lar i ty that ex i sts between these two enzymes:i n mammals,HDAC1 and HDAC2 exh i b i t approx 82% i dent i ty,and the i r g enom i c or g an i zat i on i s almost i dent i cal (15,16). Th i s i nd i cates that HDAC1 and HDAC2 arose from a relat i vely recent g ene d u pl i cat i on and s ugg ests that they have probably u nder g one l i ttle f u nct i onal d i ver g ence e i ther from the i r common ancestor or from each other (9). Indeed,both HDAC1 and HDAC2 are w i dely expressed n u clear prote i ns,they are fo u nd i n s i m i lar prote i n complexes (s ee the sect i on ent i tled HDAC1-Assoc i ated P rote i n Complexes,below),and they have been shown to heterod i mer i ze (16–18).F u rthermore,HDAC1 appears to i nfl u ence the express i on of HDAC2,and v i ce versa (s ee the sect i on ent i tled HDAC1 and the Re gu lat i on of Cell Cycle P ro g ress i on,P rol i ferat i on,and D i fferent i at i on). However,the observat i on that HDAC1 delet i on leads to embryon i c lethal i ty i n the mo u se (19)i nd i cates that,desp i te some f u nct i onal overlap,HDAC1 and HDAC2 also have d i st i nct and nonred u ndant b i olo gi cal f u nct i ons.

6Meunier and Seiser STRUCTURAL AND FUNCTIONAL

CHARACTERISTICS OF HDAC1

St ru ct ural O rgani z a t i o n and Trans c ri pt i o nal

Re gula t i o n of t h e H DA C1 Ge n e

Seq u ence analys i s and chromosomal fl u orescent in situ hybr i d i zat i on have shown that HDAC1 maps to mo u se chromosome 4 and h u man chro-mosome 1p34.1;i n both cases,l i nka g e to the g enes encod i n g the myr i s-toylated alan i ne-r i ch prote i n C k i nase s u bstrate (MARCKS)-related prote i n (MR P) and lymphocyte-spec i f i c prote i n tyros i ne k i nase (LCK) i s conserved (5,15). In mammals,the HDAC1 g ene i s abo u t 30 kb i n len g th and compr i ses 14 exons i nterr u pted by 13 i ntrons (15). The HDAC1 open read i n g frame i s 1446 bp lon g and encodes a 482-am i no ac i d prote i n w i th a molec u lar mass of approx 55 kDa (3–5).

The HDAC1 promoter i s r i ch i n GC,lacks a TATA box consens u s seq u ence,and conta i ns two transcr i pt i on factor b i nd i n g s i tes that are cr u-c i al for i ts f u ll act i v i ty:a CCAAT box that i s reco g n i zed by the transcr i p-t i onal re gu lator NF-Y and a d i stal GC box to wh i ch members of the S P fam i ly can b i nd (20). NF-Y and S P1/S P3 have been fo u nd to re gu late the transcr i pt i onal act i vat i on or repress i on of HDAC1 syner gi st i cally by recr ui t i n g e i ther h i stone acetyltransferases (HATs) or HDACs,respec-t i vely,to the HDAC1 promoter. Th i s i nd i cates that the HDAC1 g ene i tself i s re gu lated by the balanced act i on of acetylat i n g and deacetylat i n g enzymes. In part i c u lar,HDAC1 has been fo u nd to be recr ui ted to i ts own promotor by NF-Y and S P1/S P3,thereby med i at i n g i ts own repress i on v i a a ne g at i ve feedback loop (20). HDAC1 transcr i pt i on has also been shown to be i nd u ced by a two-step mechan i sm i nvolv i n g stab i l i zat i on of h i stone H3 phosphoacetylat i on by g rowth factor-med i ated act i vat i on of the m i to g en-act i vated prote i n (MA P) k i nase pathway and removal of HDACs and/or recr ui tment of HATs at the HDAC1 promoter (21).

St ru ct ural and Fun ct i o nal O rgani z a t i o n

of t h e H DA C1 P r ote in

HDAC1 i s a metalloenzyme conta i n i n g three i mportant f u nct i onal doma i ns:(1) an N-term i nal HDAC assoc i at i on doma i n (HAD; res i d u es 1–53),wh i ch i s essent i al for HDAC1 homod i mer i zat i on,assoc i at i on w i th HDAC2 as well as other prote i ns,and catalyt i c act i v i ty (18); (2) a central z i nc-b i nd i n g catalyt i c doma i n termed HDAC consens u s mot i f (res i d u es 25–303),wh i ch conta i ns several conserved h i st i d i ne and aspartate res i d u es and forms the act i ve s i te pocket of the enzyme (18,22); and (3) a C-term i nal lys i ne-r i ch doma i n (res i d u es 438–482) conta i n i n g the core n u clear local-i zat i on s ig nal (NLS) KKAKRVKT (18)and the IACEE mot i f i nvolved i n

Chapter 1 /HDAC17 the i nteract i on w i th the pocket prote i ns pRB,p107,and p130 (23–25). Interest i n g ly,a tr u ncated HDAC1 prote i n lack i n g the NLS can st i ll translo-cate i nto the n u cle u s thro ug h assoc i at i on w i th an i ntact HDAC1 prote i n

(18),and Tapl i ck and collea gu es (18)have therefore proposed that homod-

i mer i zat i on plays a p i votal role i n the act i v i ty of the enzyme. The HDAC1 prote i n i s also a tar g et for var i o u s posttranslat i onal mod i f i cat i ons (26–28). P hosphorylat i on of ser i ne res i d u es i n the C-term i nal port i on of the prote i n appears to promote HDAC1 enzymat i c act i v i ty (27),whereas s u moylat i on of lys i ne res i d u es i n the same doma i n seems to be req ui red for transcr i p-t i onal repress i on by HDAC1 (28). Acetylat i on of the prote i n also appears to enhance i ts enzymat i c act i v i ty (J. Tapl i ck and C. Se i ser,u np u bl i shed data).

TRANSCRIPTIONAL REPRESSION MEDIATED

BY HDAC1

H DA C1 S ubs t ra te Spec i f i c i t y

HDACs are bel i eved to repress transcr i pt i on ma i nly thro ug h deacetyla-t i on of the h i stone ta i ls that protr u de from the n u cleosomes,res u lt i n g i n local mod i f i cat i on of chromat i n str u ct u re (7). HDAC1 has been shown to deacetylate all fo u r core h i stones i n v i tro and appears to preferent i ally deacetylate spec i f i c lys i ne res i d u es on h i stone H4 (29). The enzyme has also been fo u nd to deacetylate a s u bset of h i stones H3 and H4 i n v i vo (19). In add i t i on to h i stones,HDAC1 can also deacetylate nonh i stone prote i ns, s u ch as the t u mor s u ppressor p53 (30,31),the transcr i pt i on factors E2F1 (32,33)and YY1 (34),and prol i ferat i n g cell n u clear ant ig en (P CNA) (35).

H DA C1-Ass oc ia te d P r ote in Co m p l e x e s

HDAC1,to g ether w i th the closely related enzyme HDAC2,i s g enerally fo u nd i n m u lt i prote i n complexes that are recr ui ted to DNA by var i o u s transcr i pt i on factors. To date,three complexes conta i n i n g HDAC1 and HDAC2 have been character i zed i n mammals:the corepressor complex SIN3,the n u cleosome remodel i n g and deacetylase complex (N u RD),and the CoREST complex (8). The SIN3 and N u RD complexes both conta i n HDAC1,HDAC2,ret i noblastoma-assoc i ated prote i n (RbAp)46,and RbAp48,a prote i n or igi nally cop u r i f i ed w i th h u man HDAC1 (3). In add i-t i on,mS i n3A,SA P18,and SA P30 are assoc i ated w i th the SIN3 complex, whereas M i-2α/M i-2β(also called CHD3/CHD4) and MTA2 are fo u nd i n the N u RD complex. The CoREST complex also conta i ns both HDAC1 and HDAC2,as well as CoREST and LSD1,a recently i dent i f i ed lys i ne-spec i f i c h i stone demethylase (8,35a).

A lar g e n u mber of transcr i pt i on factors have been i dent i f i ed that recr ui t HDAC1-assoc i ated complexes to spec i f i c promoters i n order to med i ate

8Meunier and Seiser transcr i pt i onal repress i on. These i ncl u de re gu lators of cell cycle pro g res-s i on,prol i ferat i on,d i fferent i at i on,and development (7,8,16,36,37). In add i t i on to transcr i pt i onal repress i on thro ug h prote i n complexes,HDAC1 can also f u lf i l i ts repress i ve f u nct i on thro ug h d i rect i nteract i on w i th DNA b i nd i n g prote i ns s u ch as S P1/S P3,YY1,P CNA,the pocket prote i ns pRB, p107,and p130,and the t u mor s u ppressors p53 and BRCA1 (7,30,38).

HDAC1 AND THE REGULATION OF CELL

CYCLE PROGRESSION, PROLIFERATION,

AND DIFFERENTIATION

HDAC1 was or igi nally i dent i f i ed i n the mo u se as a g rowth factor-i nd u c i ble prote i n (4)and i ts express i on has been fo u nd to correlate w i th prol i ferat i on i n var i o u s t i ss u es,embryon i c stem (ES) cells,and several transformed cell l i nes (4,19),thereby s ugg est i n g a l i nk between HDAC1 and re gu lat i on of cell u lar prol i ferat i on. Indeed,both overexpress i on of HDAC1 i n mo u se f i broblasts and d i sr u pt i on of the g ene i n mo u se embryos and ES cells have been shown to severely pert u rb prol i ferat i on and cell cycle pro g ress i on (4,19),i nd i cat i n g that ma i ntenance of cell type-spec i f i c deacetylase levels i s cr u c i al for u nrestr i cted prol i ferat i on. In l i ne w i th th i s i dea,HDAC2 and HDAC3 prote i n levels have been fo u nd to be u pre gu-lated i n the absence of HDAC1 (19),and loss of HDAC2 appears to ca u se overexpress i on of HDAC1 (S. Ch i occa,personal comm u n i cat i on). It i s, however,i mportant to note that the effects of HDAC1-med i ated transcr i p-t i onal repress i on on the re gu lat i on of cell cycle pro g ress i on,prol i ferat i on, and d i fferent i at i on are d i verse and seem to be dependent on HDAC1 molec u lar partners,as w i ll be d i sc u ssed i n the follow i n g sect i ons.

H DA C1 and t h e Poc k et P r ote ins

The i nvolvement of HDAC1 i n the control of cell cycle pro g ress i on i s u nderscored by i ts i nteract i on w i th the three members of the ret i noblas-toma fam i ly of transcr i pt i onal repressors,the pocket prote i ns pRB,p107, and p130,v i a the IACEE mot i f (23–25,39,40). Hypophosphorylated pocket prote i ns recr ui t HDAC1 early i n G1 and repress cell cycle pro g res-s i on by b i nd i n g to and i nh i b i t i n g members of the E2F fam i ly of transcr i p-t i on factors. Upon phosphorylat i on of pocket prote i ns by cycl i n-dependent k i nase (CDK)/cycl i n complexes,the HDAC1/pocket prote i n/E2F complex i s abro g ated,allow i n g E2F factors to act i vate a ser i es of g enes req ui red for G1/S phase trans i t i on and DNA synthes i s,i ncl u d i n g cycl i n A and cycl i n E (41). CDK4/6/cycl i n D2 complexes have been shown to be par-t i c u larly effect i ve at phosphorylat i n g pRB and conseq u ently i nh i b i t i n g the pRB-HDAC1 i nteract i on at the G1/S phase trans i t i on,th u s promot i n g cycl i n E express i on (42). Altho ug h recr ui tment of HDAC1 by pRB i s

Chapter 1 /HDAC19 clearly cr u c i al for repress i on of E2F-respons i ve g enes,a recent report has shown that HDAC1 does not cooperate w i th pRB to repress E2F1-med i ated cell death. In contrast,i n th i s part i c u lar case,HDAC1 i nh i b i ts the effects of pRB on E2F1 by a mechan i sm that does not i nvolve deacety-lase act i v i ty b u t req ui res the IACEE mot i f (43).

H DA C1 and t h e MAD/MA X Hete r o dim e r

A f u rther i nd i cat i on of the role of HDAC1 i n the control of cell g rowth and prol i ferat i on i s i ts assoc i at i on w i th the MAD/MAX heterod i mer. In prol i ferat i n g cells,MYC/MAX heterod i mer act i vates transcr i pt i on of g enes req ui red for cell u lar g rowth. Upon d i fferent i at i on,however,MYC i s replaced by MAD,and the MAD/MAX heterod i mer represses transcr i p-t i on of the g rowth-st i m u latory g enes thro ug h recr ui tment of the SIN3/HDAC1/2 corepressor complex (44–47).

P r o m ot i o n of Ce llular P r o li fe ra t i o n by H DA C1 The recr ui tment of HDAC1 by the pocket prote i ns and the MAD/MAX complex clearly demonstrates the i nvolvement of the prote i n i n repress i on of cell u lar prol i ferat i on. However,tar g eted d i sr u pt i on of HDAC1 i n the mo u se has revealed that the enzyme i s also essent i al for u nrestr i cted pro-l i ferat i on(19). HDAC1 homozy g o u s m u tant (–/–) embryos are severely g rowth retarded and exh i b i t a prol i ferat i on defect that i s assoc i ated w i th elevated levels of the CDK i nh i b i tors p21and p27 and w i th a decrease i n cycl i n-assoc i ated act i v i ty.S i m i lar phenotypes were also observed i n HDAC1–/– ES cells. Cons i stent w i th these f i nd i n g s,the p21 promoter has been fo u nd to be assoc i ated w i th hyperacetylated h i stones i n the absence of HDAC1 (19),and HDAC1 has been shown to be recr ui ted to the p21 promoter by d i rect i nteract i on w i th the transcr i pt i on factor S P1 (48). The t u mor s u ppressor p53 i s known to act i vate p21 i n response to DNA dam-a g es,thereby i nd u c i n g cell cycle arrest and apoptos i s (49). Interest i n g ly, p53 i s also recr ui ted to the p21 promoter thro ug h d i rect i nteract i on w i th S P1(48,50)and has been shown to compete w i th HDAC1 for the re gu la-t i on of p21 express i on follow i n g DNA dama g e (48). Taken to g ether,these f i nd i n g s i nd i cate that HDAC1 i s a cr u c i al ne g at i ve re gu lator of p21 tran-scr i pt i onal act i v i ty,altho ug h the poss i b i l i ty cannot be excl u ded that other HDACs may also be i nvolved i n the repress i on of p21 (51).

In add i t i on to i nh i b i t i on of p21,HDAC1 has also been shown to repress p53 f u nct i on by d i rect deacetylat i on of the prote i n (30,31). Acetylat i on of p53 stab i l i zes and act i vates the prote i n i n response to g enotox i c stress, wh i le deacetylat i on appears to prov i de a rap i d mechan i sm to i nh i b i t p53-med i ated cell cycle arrest and apoptos i s and to restore normal cell g rowth once DNA repa i r i s completed (52). Th i s probably occ u rs thro ug h recr ui tment of HDAC1 by MDM2—a key ne g at i ve re gu lator

10Meunier and Seiser of p53—thereby i nd u c i n g p53 deacetylat i on and allow i n g MDM2 to u b i q-ui t i nate the prote i n,wh i ch i s then tar g eted for de g radat i on (53). Altho ug h acetylat i on clearly act i vates p53 f u nct i on,i t appears not to be essent i al for the transact i vat i on of p21 follow i n g DNA dama g e; however,p53 acetyla-t i on stron g ly enhances i ts b i nd i n g to the p21 promoter i n v i vo (52,54).

H DA C1 and Nu c l e ar Recepto rs

N u clear receptors are a lar g e fam i ly of l ig and-i nd u ced transcr i pt i on factors that re gu late a var i ety of phys i olo gi cal processes,i ncl u d i n g devel-opment and d i fferent i at i on.F u rthermore,n u clear receptors are well-character i zed examples of HDAC-recr ui t i n g prote i ns (55). Thyro i d hormone receptors and ret i no i c ac i d receptors have been shown to repress transcr i p-t i on thro ug h recr ui tment of the SIN3/HDAC1/2 complex i n the absence of l ig and(7). HDAC1 has also been fo u nd to assoc i ate w i th a var i ety of tran-scr i pt i onal cofactors that b i nd to and block n u clear receptors i n the pres-ence of a g on i sts,s u ch as MTA1 (56),receptor-i nteract i n g prote i n 140 (RI P140;57),and the repressor of estro g en receptor act i v i ty (REA;58).

F u rthermore,a recent report has shown that HDAC1 can d i rectly i nteract w i th and s u ppress the transcr i pt i onal act i v i ty of estro g en receptor-α(ER-α) i n breast cancer cells (59).

H DA C1 and Di ffe r e n t ia t i o n P r oce ss e s

The i nvolvement of HDAC1 i n d i fferent i at i on processes i s h ig hl ig hted by i ts i nteract i on w i th the myo g en i c act i vator MyoD. In u nd i fferent i ated myoblasts,HDAC1 assoc i ates w i th MyoD,lead i n g to repress i on of g enes i nvolved i n skeletal m u scle d i fferent i at i on. Upon i nd u ct i on of myoblast d i fferent i at i on,the i nteract i on between HDAC1 and MyoD i s abro g ated,allow i n g MyoD to act i vate the myo g en i c pro g ram (60,61). It has been shown that hypophosphorylated pRB can d i splace HDAC1 from MyoD u pon d i fferent i at i on,thereby red u c i n g the repress i ve effect of HDAC1 on MyoD; s u bseq u ently,HDAC1/pRB complexes are fo u nd i n d i fferent i ated myot u bes,where they appear to ma i nta i n i rrevers i ble cell cycle arrest (61). In part i c u lar,Mal and Harter (62)have shown that HDAC1 and MyoD are present at the myo g en i n promoter i n u nd i fferen-t i ated myoblasts and that replacement of HDAC1 by the HAT P/CAF leads to MyoD-med i ated d i fferent i at i on,thereby s ugg est i n g that acetyla-t i on i s an i mportant step i n skeletal m u scle d i fferent i at i on. Recently,a role for HDAC1 and HDAC2 i n the re gu lat i on of i ntest i nal ep i thel iu m d i fferent i at i on has also been demonstrated i n v i vo:express i on of both prote i ns was fo u nd to decrease u pon d i fferent i at i on of the i ntest i nal ep i thel iu m,whereas the i r overexpress i on blocked the express i on of certa i n d i fferent i at i on markers (63).

Chapter 1 /HDAC111

OTHER BIOLOGICAL FUNCTIONS OF HDAC1 Transcr i pt i onal repress i on med i ated by HDAC1 clearly plays a cr u c i al role i n re gu lat i on of cell cycle pro g ress i on,prol i ferat i on,and d i fferent i a-t i on. However,i ncreas i n g ev i dence i nd i cates that HDAC1 can also i nfl u-ence var i o u s other b i olo gi cal processes by mechan i sms that do not necessar i ly i nvolve transcr i pt i onal repress i on,as w i ll be d i sc u ssed i n the follow i n g sect i ons.

H DA C1 and DNA Rep li c a t i o n

P CNA i s a cr u c i al component of the DNA repl i cat i on mach i nery (64).P hys i cal i nteract i on between HDAC1 and P CNA has been fo u nd to ca u se deacetylat i on of the prote i n and appears to be l i nked to d i sso-c i at i on of P CNA from the DNA and complet i on of repl i cat i on (35,38). Th i s s ugg ests that HDAC act i v i ty i s essent i al for the format i on of proper chromat i n str u ct u re follow i n g DNA synthes i s. Whether deacetylat i on i s the ca u se,or the conseq u ence,of P CNA d i ssoc i at i on from the DNA polymerase rema i ns,however,to be el u c i dated. HDAC1 has also been shown to i nteract d i rectly w i th the enzyme DNA topo i somerase II i n the context of the N u RD complex (65,66). Topo i somerase II i s i nvolved i n DNA u nw i nd i n g d u r i n g repl i cat i on and transcr i pt i on and also part i c-i pates i n g enet i c recomb i nat i on,chromosome condensat i on,and apop-tos i s(67). The assoc i at i on between the two enzymes appears to be essent i al for apoptos i s i nd u ced by the DNA topo i somerase II po i son epos i de,and i t has been proposed that chromat i n remodel i n g by the N u RD/HDAC1 complex i s necessary for topo i somerase II-med i ated DNA rearran g ements (66).

H DA C1 and t h e G2/M C h ec k po in t

A l i nk between HDAC1 and the G2/M checkpo i nt has been s ugg ested by the f i nd i n g that the enzyme forms a complex w i th H u s1 and Rad9,two Rad prote i ns that are i nvolved i n the m i tot i c checkpo i nt i nd u ced by DNA dama g e or DNA repl i cat i on block (68). It has been proposed that the Rad prote i ns/HDAC1 complex co u ld assoc i ate w i th P CNA to form a r i n g-l i ke str u ct u re aro u nd the DNA at the G2/M checkpo i nt. Th i s complex co u ld then recr ui t the n u cleosome remodel i n g N u RD complex to fac i l i tate DNA repa i r and/or restore the nat i ve chromat i n conformat i on once DNA has been repa i red (68).

Add i t i onal ev i dence for the i nvolvement of HDAC1 i n m i tot i c processes comes from the observat i on that the prote i n assoc i ates w i th h u man and mo u se metaphase centromeres,as well as w i th all other major re gi ons of per i centr i c and nonper i centr i c heterochromat i n (69). In part i c u lar, HDAC1 and MBD3,a component of the N u RD complex,have been fo u nd

12Meunier and Seiser to colocal i ze w i th A u rora A,a k i nase that i s cr u c i al for centrosome sepa-rat i on and b i polar sp i ndle assembly (70),at the centrosomes i n the early M phase (71). F u rthermore,the SIN3/HDAC1/2 complex-assoc i ated pro-te i n Sds3 has recently been shown to be essent i al for deacetylat i on of per i-centr i c heterochromat i n h i stones and proper chromosome se g re g at i on (72),s ugg est i n g that HDAC1 and/or HDAC2 play an i mportant role i n m i tot i c processes.

H DA C1 and C hr o ma t in M o di f i c a t i o ns

Increas i n g ev i dence i nd i cates that HDAC1 i s an i ntr i ns i c part of the ep ig enet i c c i rc ui t re gu lat i n g chromat i n mod i f i cat i on and remodel i n g. Cons i stent w i th th i s i dea,var i o u s reports have shown that HDAC1 i nter-acts w i th several other chromat i n and DNA-mod i fy i n g enzymes. F or i nstance,i t has recently been reported that HDAC1 i s recr ui ted by the HAT p300 and i nterferes w i th the p300-dependent transcr i pt i onal act i va-t i on of p53 and MyoD,thereby s ugg est i n g that HATs and HDACs co u ld assoc i ate to control g ene express i on (73). A l i nk between h i stone methyla-t i on and deacetylat i on has been demonstrated by the f i nd i n g that HDAC1, HDAC2,and HDAC3 i nteract w i th the h i stone methyltransferase S u v39H1 (74). Assoc i at i on of HDACs and S u v39H1 co u ld play a role i n hete-rochromat i n s i lenc i n g and/or transcr i pt i onal repress i on by pRB. In add i-t i on,the P olycomb g ro u p (P cG) complex EED/EZH2 has been fo u nd to i nteract w i th HDAC1 and HDAC2 (75). The EED-EZH2 complex med i-ates transcr i pt i onal repress i on i n part v i a i ts i ntr i ns i c h i stone methyltrans-ferase act i v i ty (76),and i ts s i lenc i n g f u nct i on appears to req ui re HDAC act i v i ty (75). Recently,work by Sh i and collea gu es (76a)has also ra i sed the poss i b i l i ty that,w i th i n the CoREST complex,the HDAC act i v i ty of HDAC1 and HDAC2 may collaborate w i th the h i stone demethylase act i v i ty of LSD1 to create a repress i ve chromat i n env i ronment. Confl i ct i n g res u lts have however been reported (76b)and d i screpanc i es between the two st u d i es st i ll need to be resolved.

In add i t i on to h i stone methylat i on,DNA methylat i on has also been fo u nd to cooperate w i th h i stone deacetylat i on to mod u late chromat i n remodel i n g and transcr i pt i onal s i lenc i n g(77). Methyl-CpG b i nd i n g pro-te i ns s u ch as MeC P2 and MBD2 have been shown to i nteract w i th HDAC1 and to repress transcr i pt i on i n an HDAC-dependent manner (77).

F u rthermore,HDAC1 has been fo u nd to med i ate transcr i pt i onal repres-s i on thro ug h assoc i at i on w i th the DNA methyltransferases DNMT1 (78,79),DNMT3A (80),DNMT3B (81),and DNMT3L (82). In part i c u lar, HDAC1 has been shown to form a complex w i th DNMT1,pRB,and E2F1 to repress transcr i pt i on from promoters conta i n i n g E2F1 b i nd i n g s i tes(79).

Chapter 1 /HDAC113

D efe ns e M ec hanisms Agains t Viral I n fect i o n

In recent years,ev i dence has emer g ed that HDAC1 i s i nvolved i n cell u lar defense a g a i nst v i ral i nfect i on. For example,v i ral transcr i pt i on med i ated by open read i n g frame 50 (ORF50),an act i vator of early and late g enes i n the lyt i c cycle of the Kapos i’s sarcoma-assoc i ated her-pesv i r u s,i s repressed u pon assoc i at i on w i th HDAC1 (83,84). F u rthermore, i nh i b i t i on of HDAC act i v i ty appears to be i mportant for v i ral i nfect i on. For example,Gam1,an early g ene prod u ct essent i al for the repl i cat i on of the av i an adenov i r u s CELO,can i nteract w i th HDAC1 and i nh i b i t i ts enzy-mat i c act i v i ty (85). The bov i ne herpesv i r u s 1 i mmed i ate-early prote i n (bIC P0) has also been shown to assoc i ate w i th HDAC1 and act i vate tran-scr i pt i on by i nterfer i n g w i th MAD/MAX-dependent transcr i pt i onal repres-s i on,thereby promot i n g v i ral i nfect i on i n d i fferent i ated cells (86). V i ral transform i n g prote i ns s u ch as the h u man pap i llomav i r u s oncoprote i n E7 are also known to i nterfere w i th the b i nd i n g of HDAC1 to pRB,thereby promot i n g cell cycle pro g ress i on (23–25). Altho ug h block i n g of HDAC act i v i ty appears to be i mportant for v i ral act i v i ty,i t may also have ne g at i ve conseq u ences for the v i r u s,as HDAC i nh i b i t i on has been reported to act i-vate cell u lar mechan i sms to f ig ht a g a i nst the v i ral i nfect i on (87). In l i ne w i th th i s i dea,a recent cl i n i cal st u dy by Lerhman and collea gu es (87a) has s ugg ested that i nh i b i t i on of HDAC1 i n rest i n g CD4+ T cells co u ld contr i b u te to el i m i nat i on of h u man i mm u nodef i c i ency v i r u s (HIV) i nfect i on i n h u man pat i ents.

H DA C1 I s Ess e n t ial fo r M o us e Embry o ni c D e v e l op m e n t

Var i o u s st u d i es have demonstrated the role of the HDAC1-conta i n i n g complexes SIN3 and N u RD i n spec i f i c developmental processes (36). D i rect ev i dence for the cr u c i al role of HDAC1 i tself d u r i n g embryon i c develop-ment comes from the analys i s of an HDAC1 knocko u t mo u se model (19). Whereas the absence of one HDAC1 allele does not i mpa i r mo u se v i ab i l i ty, tar g eted d i sr u pt i on of both HDAC1 alleles severely pert u rbs embryon i c development and leads to lethal i ty before E10.5. In add i t i on to red u ced cell u lar prol i ferat i on (s ee sect i on ent i tled P romot i on of Cell u lar P rol i ferat i on by HDAC1),HDAC1–/– embryos d i splay var i o u s developmental defects s u ch as abnormal head and allanto i s format i on. Altho ug h i ncreased levels of HDAC2 and HDAC3 prote i ns have been fo u nd i n HDAC1–/– embryos and ES cells,these two class I enzymes co u ld not complement the loss of HDAC1. Accord i n g ly,the deacetylase act i v i ty of the SIN3 and N u RD com-plexes was s ig n i f i cantly red u ced i n HDAC1–/– ES cells (19). Taken to g ether, these f i nd i n g s i nd i cate that HDAC1 plays a cr u c i al and u n i q u e role d u r i n g mo u se embryon i c development and that the i nte g r i ty of HDAC1-conta i n i n g complexes i s essent i al for proper development.

14Meunier and Seiser Add i t i onal ev i dence for the cr u c i al role of HDAC1 d u r i n g development comes from the analys i s of HDAC1 m u tat i on i n other or g an i sms. M u tat i on of the HDAC1 ortholo g R P D3 i n D ro s o phila m e lan o gast er pert u rbs se g-mentat i on and res u lts i n embryon i c lethal i ty (88). In Ca e n or ha b ditis e l e gans, i nh i b i t i on of maternal and zy g ot i c HDA-1 express i on also leads to embry-on i c lethal i ty (89),whereas m u tat i on of zy g ot i c HDA-1 only ca u ses defects i n postembryon i c g onado g enes i s (90). Embryon i c lethal i ty i s also assoc i ated w i th delet i on of HDAC1 i n Dani o rer i o(91),and a deta i led analys i s of the m u tant phenotype has revealed that HDAC1 i s spec i f i cally req ui red to ma i nta i n ne u ro g enes i s i n the zebraf i sh central nervo u s system d u r i n g embryo g enes i s (12).

H DA C1 and C an ce r

Extens i ve st u d i es have shown that HDAC i nh i b i tors i nd u ce cell cycle arrest,d i fferent i at i on,and/or apoptos i s i n a var i ety of transformed cell l i nes,as well as i n t u mor-bear i n g an i mals. Conseq u ently,these i nh i b i tory compo u nds are c u rrently i n phase I and II cl i n i cal tr i als for ant i t u mor ther-apy (92,93). Several mechan i sms can be proposed to expla i n the ant i t u mor effects of HDAC i nh i b i tors. The g eneral v i ew i s that acc u m u lat i on of acetylated h i stones and nonh i stone prote i ns leads to act i vat i on or repres-s i on of a spec i f i c s u bset of g enes and molec u lar pathways cr u c i al for repress i on of t u mor cell g rowth. Th i s mechan i sm i s cons i stent w i th the f i nd i n g that the express i on of only a l i m i ted n u mber of g enes i s affected by HDAC i nh i b i tors (94). W i th i ncreas i n g ev i dence for HDACs i nvolve-ment i n molec u lar and cell u lar processes other than transcr i pt i onal re gu la-t i on,i t i s also reasonable to hypothes i ze that HDAC i nh i b i tors exert the i r effects by d i rectly i nterfer i n g w i th DNA repl i cat i on or m i tot i c d i v i s i on.

F i nally,based on the observat i on that t u mor cells (wh i ch by def i n i t i on exh i b i t alterat i ons i n var i o u s molec u lar pathways i nvolved i n cell g rowth and d i fferent i at i on) are m u ch more sens i t i ve to the effects of HDAC i nh i b i tors than normal cells (92),we propose that act i vat i on or repress i on of spec i f i c g enes and pathways by HDAC i nh i b i tors may g enerate con-fl i ct i n g s ig nals i n t u mor cells,lead i n g to cell death or apoptos i s.

The ant i t u mor effects of HDAC i nh i b i tors clearly s ugg est that HDACs play a major role i n cancer development. However,as most HDAC i nh i b i tors affect the act i v i ty of several enzymes,i t i s d i ff i c u lt to i dent i fy the part i c u lar HDACs i nvolved i n t u mor format i on. One way to eval u ate the i mportance of spec i f i c HDACs i n cancer i s thro ug h analys i s of the i r express i on levels i n t u mors. Recent reports have i nd i cated that HDAC1 i s u pre gu lated i n g astr i c and prostate cancers (95–98),and i n both cases,i ts overexpress i on has been shown to correlate w i th downre gu lat i on of g elsol i n (97,98),a known tar g et of HDAC i nh i b i tors (94). F u rthermore,HDAC1 knockdown i n h u man cerv i cal carc i noma cells has been fo u nd to i nd u ce chan g es i n cell u lar morpholo g y and to i nh i b i t prol i ferat i on,thereby

Chapter 1 /HDAC115 s ugg est i n g that HDAC1 i s essent i al for t u mor cell s u rv i val (99). Interest i n g ly,downre gu lat i on of HDAC1 express i on has been shown to be assoc i ated w i th cell u lar d i fferent i at i on i n a var i ety of h u man breast t u mor cell l i nes (100).

One mechan i sm by wh i ch HDAC i nh i b i tors appear to repress t u mor cell g rowth i s thro ug h the act i vat i on of the t u mor s u ppressor p21,wh i ch i s req ui red for i nh i b i t i on of cell cycle pro g ress i on (92). As noted above (s ee sect i on ent i tled P romot i on of Cell u lar P rol i ferat i on by HDAC1),HDAC1 i s a cr u c i al ne g at i ve re gu lator of p21. A recent report has shown that tran-scr i pt i onal act i vat i on of p21 by the HDAC i nh i b i tor s u beroylan i l i de hydroxam i c ac i d (SAHA) i s accompan i ed by a marked red u ct i on i n HDAC1 bo u nd at the p21 promoter (51). F u rthermore,d i splacement of HDAC1 from the p21 promoter by the pRB b i nd i n g prote i n Che-1 (101,102)has been shown to act i vate p21 and conseq u ently i nh i b i t prol i f-erat i on i n h u man colon carc i noma cell l i nes (103). Taken to g ether,these f i nd i n g s stron g ly s ugg est that HDAC1 co u ld promote t u mor format i on thro ug h select i ve repress i on of p21. Another mechan i sm by wh i ch HDAC1 co u ld promote t u mor ig enes i s i s v i a s u ppress i on of ER-α(s ee the sect i on ent i tled HDAC1 and N u clear Receptors),whose loss i s known to be cr i t i cal for breast cancer pro g ress i on (59).F i nally,i t has been reported that HDAC1 express i on can be i nd u ced by hypox i a i n a l u n g carc i noma cell l i ne,lead i n g to downre gu lat i on of the t u mor s u ppressors p53 and von H i ppel-L i nda u factor and st i m u lat i on of hypox i a-i nd u ced an gi o g enes i s (104). These f i nd i n g s s ugg est that HDAC1 co u ld i nfl u ence t u mor pro g res-s i on by promot i n g an gi o g enes i s.

CONCLUDING REMARKS AND FUTURE DIRECTIONS The cr u c i al role of HDAC1 i n the re gu lat i on of cell cycle pro g ress i on, prol i ferat i on,and d i fferent i at i on v i a transcr i pt i onal repress i on of spe-c i f i c tar g et g enes has clearly been demonstrated s i nce the i dent i f i cat i on of the prote i n i n 1996. In add i t i on,ev i dence has recently emer g ed show-i n g that HDAC1 can i nfl u ence var i o u s cell u lar processes,s u ch as DNA repl i cat i on and chromosome se g re g at i on,i ndependently of transcr i p-t i onal repress i on. Moreover,HDAC1-med i ated transcr i pt i onal act i vat i on of i nterferon-st i m u lated g enes (ISGs) has recently been reported (105,106)and HDAC1 w i th i ts assoc i ated enzymat i c act i v i ty has been fo u nd to be necessary for the proper i nd u ct i on of the ISGs i nterferon re gu latory factor 1 (IRF1) and gu anylate b i nd i n g prote i n 2 (GB P2) (G. Z u pkov i tz and C. Se i ser,u np u bl i shed data). Importantly,c u m u lat i ve observat i ons i nd i cate that HDAC1 i s i nvolved i n t u mor format i on and/or pro g ress i on and i s a cr u c i al tar g et for HDAC i nh i b i tors i n cancer therapy. The development of select i ve i nh i b i tors i s cr i t i cal to better u nderstand the exact role played by HDAC1 i n normal and neoplast i c cells. In th i s

16Meunier and Seiser

respect,i t i s i nterest i n g to note that the HDAC i nh i b i tors MS-27-275 and SB-429201 have recently been shown to preferent i ally i nh i b i t HDAC1 (107)and so may prove extremely u sef u l for f u t u re analyses of the b i olo gi cal f u nct i ons of HDAC1.

ACKNOWLEDGMENTS

We thank B. Sch u etten g r u ber and S. W i nter for cr i t i cal comments on the man u scr i pt and S. Ch i occa for shar i n g u np u bl i shed data. We apolo-gi ze to all a u thors whose work co u ld not be referenced ow i n g to space l i m i tat i ons. Th i s work was s u pported by the A u str i an Sc i ence F u nd (FWF g rant P14909-B12) and the GEN-AU pro g ram of the A u str i an Government.

REFERENCES

1.K i j i ma M,Yosh i da M,S ugi ta K,Hor i no u ch i S,Bepp u T. Trapox i n,an ant i t u mor

cycl i c tetrapept i de,i s an i rrevers i ble i nh i b i tor of mammal i an h i stone deacety-lase. J B i ol Chem 1993;268:22,429–22,435.

2.Yosh i da M,Hor i no u ch i S,Bepp u T. Tr i chostat i n A and trapox i n:novel chem i cal

probes for the role of h i stone acetylat i on i n chromat i n str u ct u re and f u nct i on.

B i oessays 1995;17:423–430.

3.Ta u nton J,Hass ig CA,Schre i ber SL. A mammal i an h i stone deacetylase related

to the yeast transcr i pt i onal re gu lator Rpd3p. Sc i ence 1996;272:408–411.

4.Bartl S,Tapl i ck J,La gg er G,Kh i er H,K u chler K,Se i ser C. Ident i f i cat i on of

mo u se h i stone deacetylase 1 as a g rowth factor-i nd u c i ble g ene. Mol Cell B i ol 1997;17:5033–5043.

5.F u r u kawa Y,Kawakam i T,S u do K,et al. Isolat i on and mapp i n g of a h u man

g ene (R P D3L1) that i s homolo g o u s to R P D3, a transcr i pt i on factor i n

Sa cc ha ro my ce s cere visia e. Cyto g enet Cell Genet 1996;73:130–133.

6.V i dal M,Gaber RF. R P D3 encodes a second factor req ui red to ach i eve max i-

m u m pos i t i ve and ne g at i ve transcr i pt i onal states i n Sa cc ha ro my ce s cere visia e.

Mol Cell B i ol 1991;11:6317–6327.

7.Cress WD,Seto E. H i stone deacetylases,transcr i pt i onal control,and cancer.

J Cell P hys i ol 2000;184:1–16.

8.Groz i n g er CM,Schre i ber SL. Deacetylase enzymes:b i olo gi cal f u nct i ons and

the u se of small-molec u le i nh i b i tors. Chem B i ol 2002;9:3–16.

9.Gre g orett i IV,Lee YM,Goodson HV. Molec u lar evol u t i on of the h i stone

deacetylase fam i ly:f u nct i onal i mpl i cat i ons of phylo g enet i c analys i s. J Mol B i ol 2004;338:17–31.

10.S u n JM,Chen HY,Mon i wa M,Sam u el S,Dav i e JR.Pu r i f i cat i on and character-

i zat i on of ch i cken erythrocyte h i stone deacetylase 1. B i ochem i stry 1999;38:

5939–5947.

https://www.360docs.net/doc/f03961292.html,domery M,Lyons S,Sommerv i lle J.Xe n o pus HDm,a maternally expressed

h i stone deacetylase,belon g s to an anc i ent fam i ly of acetyl-metabol i z i n g

enzymes. Gene 1997;198:275–280.

12.C u nl i ffe VT. H i stone deacetylase 1 i s req ui red to repress Notch tar g et g ene expres-

s i on d u r i n g zebraf i sh ne u ro g enes i s and to ma i nta i n the prod u ct i on of motone u-rones i n response to hed g eho g s ig nall i n g. Development 2004;131:2983–2995.

Chapter 1 /HDAC117 13.Ross i V,Hart i n g s M,Motto M. Ident i f i cat i on and character i zat i on of an R P D3

homolo gu e from ma i ze (Ze a mays L.) that i s able to complement an rpd3 n u ll m u tant of Sa cc ha ro my ce s cere visia e. Mol Gen Genet 1998;258:288–296.

14.Lechner T,L u sser A,Pi pal A,et al. R P D3-type h i stone deacetylases i n ma i ze

embryos. B i ochem i stry 2000;39:1683–1692.

15.Kh i er H,Bartl S,Sch u etten g r u ber B,Se i ser C. Molec u lar clon i n g and character-

i zat i on of the mo u se h i stone deacetylase 1 g ene:i nte g rat i on of a retrov i r u s i n

129SV m i ce. B i och i m B i ophys Acta 1999;1489:365–373.

16.de R ui jter AJM,van Genn i p AH,Caron HN,Kemp S,van K ui lenb u r g AB P.

H i stone deacetylases (HDACs):character i zat i on of the class i cal HDAC fam i ly.

B i ochem J 2003;370:737–749.

17.Hass ig CA,Ton g JK,Fle i scher TC,et al. A role for h i stone deacetylase act i v i ty

i n HDAC1-med i ated transcr i pt i onal repress i on.P roc Natl Acad Sc i U S A

1998;95:3519–3524.

18.Tapl i ck J,K u rtev V,Kroboth K,P osch M,Lechner T,Se i ser C. Homo-ol ig omer i-

sat i on and n u clear local i sat i on of mo u se h i stone deacetylase 1. J Mol B i ol 2001;308:27–38.

https://www.360docs.net/doc/f03961292.html, gg er G,O’Carroll D,Rembold M,et al. Essent i al f u nct i on of h i stone deacety-

lase 1 i n prol i ferat i on control and CDK i nh i b i tor repress i on. EMBO J 2002;21: 2672–2681.

20.Sch u etten g r u ber B,S i mboeck E,Kh i er H,Se i ser C. A u tore gu lat i on of mo u se

h i stone deacetylase 1 express i on. Mol Cell B i ol 2003;23:6993–7004.

21.Ha u ser C,Sch u etten g r u ber B,Bartl S,La gg er G,Se i ser C. Act i vat i on of the

HDAC1 g ene by cooperat i ve h i stone phosphorylat i on and acetylat i on. Mol Cell

B i ol 2002;22:7820–7830.

22.Marmorste i n R. Str u ct u re of h i stone deacetylases:i ns ig hts i nto s u bstrate reco g-

n i t i on and catalys i s. Str u ct u re (Camb) 2001;9:1127–1133.

23.Brehm A,M i ska EA,McCance DJ,Re i d JL,Bann i ster AJ,Ko u zar i des T.

Ret i noblastoma prote i n recr ui ts h i stone deacetylase to repress transcr i pt i on.

Nat u re 1998;391:597–601.

24.Ferre i ra R,Ma g na g h i-Ja u l i n L,Rob i n P,Harel-Bellan A,Tro u che D. The three

members of the pocket prote i ns fam i ly share the ab i l i ty to repress E2F act i v i ty thro ug h recr ui tment of a h i stone deacetylase.P roc Natl Acad Sc i U S A 1998;95: 10,493–10,498.

25.Ma g na g h i-Ja u l i n L,Gro i sman R,Na gui bneva I,et al. Ret i noblastoma prote i n

represses transcr i pt i on by recr ui t i n g a h i stone deacetylase. Nat u re 1998;391: 601–605.

26.Ca i R,Kwon P,Yan-Neale Y,Samb u ccett i L,F i scher D,Cohen D. Mammal i an

h i stone deacetylase 1 prote i n i s posttranslat i onally mod i f i ed by phosphoryla-

t i on. B i ochem B i ophys Res Comm u n 2001;283:445–453.

27.P fl u m MK,Ton g JK,Lane WS,Schre i ber SL. H i stone deacetylase 1 phosphory-

lat i on promotes enzymat i c act i v i ty and complex format i on. J B i ol Chem 2001;276:47,733–47,741.

28.Dav i d G,Nept u ne MA,De Pi nho RA. SUMO-1 mod i f i cat i on of h i stone deacety-

lase 1 (HDAC1) mod u lates i ts b i olo gi cal act i v i t i es. J B i ol Chem 2002;277: 23,658–23,663.

29.Johnson CA,T u rner BM. H i stone deacetylases:complex transd u cers of n u clear

s ig nals. Sem i n Cell Dev B i ol 1999;10:179–188.

30.J u an LJ,Sh i a WJ,Chen MH,et al. H i stone deacetylases spec i f i cally down-

re gu late p53-dependent g ene act i vat i on. J B i ol Chem 2000;275:20,436–20,443.

18Meunier and Seiser 31.L u o J,S u F,Chen D,Sh i loh A,G u W. Deacetylat i on of p53 mod u lates i ts effect

on cell g rowth and apoptos i s. Nat u re 2000;408:377–381.

32.Mart i nez-Balbas MA,Ba u er UM,N i elsen SJ,Brehm A,Ko u zar i des T.

Re gu lat i on of E2F1 act i v i ty by acetylat i on. EMBO J 2000;19:662–671.

33.Marz i o G,Wa g ener C,G u t i errez MI,Cartwr ig ht P,Hel i n K,G i acca M. E2F

fam i ly members are d i fferent i ally re gu lated by revers i ble acetylat i on. J B i ol Chem 2000;275:10,887–10,892.

34.Yao YL,Yan g WM,Seto E. Re gu lat i on of transcr i pt i on factor YY1 by acetyla-

t i on and deacetylat i on. Mol Cell B i ol 2001;21:5979–5991.

35.Naryzhny SN,Lee H. The post-translat i onal mod i f i cat i ons of prol i ferat i n g cell

n u clear ant ig en:acetylat i on,not phosphorylat i on,plays an i mportant role i n the re gu lat i on of i ts f u nct i on. J B i ol Chem 2004;279:20,194–20,199.

35a.Sh i Y,Lan F,Matson C,et al. H i stone demethylat i on med i ated by the n u clear am i ne ox i dase homolo g LSD1. Cell 2004;119:941–953.

36.Ahr i n g er J. N u RD and SIN3 h i stone deacetylase complexes i n development.

Trends Genet 2000;16:351–356.

37.N g HH,B i rd A. H i stone deacetylases:s i lencers for h i re. Trends B i ochem Sc i

2000;25:121–126.

38.M i l u t i nov i c S,Zh u an g Q,Szyf M.P rol i ferat i n g cell n u clear ant ig en assoc i ates

w i th h i stone deacetylase act i v i ty,i nte g rat i n g DNA repl i cat i on and chromat i n mod i f i cat i on. J B i ol Chem 2002;277:20,974–20,978.

39.L u o RX,P ost ig o AA,Dean DC. Rb i nteracts w i th h i stone deacetylases to repress

transcr i pt i on. Cell 1998;92:463–473.

40.St i e g ler P,De L u ca A,Ba g ella L,G i ordano A. The COOH-term i nal re gi on of

pRb2/p130 b i nds to h i stone deacetylase 1 (HDAC1),enhanc i n g transcr i pt i onal repress i on of the E2F-dependent cycl i n A promoter. Cancer Res 1998;58: 5049–5052.

41.Wade P A. Transcr i pt i onal control at re gu latory checkpo i nts by h i stone deacety-

lases:molec u lar connect i ons between cancer and chromat i n. H u m Mol Genet 2001;10:693–698.

42.Takak i T,F u kasawa K,S u z u k i-Takahash i I,H i ra i H. Cdk-med i ated phosphory-

lat i on of pRB re gu lates HDAC b i nd i n g i n v i tro. B i ochem B i ophys Res Comm u n 2004;316:252–255.

43.P ennaneach V,Barb i er V,Re g azzon i K,Fotedar R,Fotedar A. Rb i nh i b i ts E2F-

1-i nd u ced cell death i n a LXCXE-dependent manner by act i ve repress i on. J B i ol Chem 2004;279:23,376–23,383.

44.Hass ig CA,Fle i scher TC,B i ll i n AN,Schre i ber SL,Ayer DE. H i stone deacety-

lase act i v i ty i s req ui red for f u ll transcr i pt i onal repress i on by mS i n3A. Cell 1997;89:341–347.

https://www.360docs.net/doc/f03961292.html,herty CD,Yan g WM,S u n JM,Dav i e JR,Seto E,E i senman RN. H i stone

deacetylases assoc i ated w i th the mS i n3 corepressor med i ate mad transcr i pt i onal repress i on. Cell 1997;89:349–356.

46.Sommer A,H i lfenha u s S,Menkel A,et al. Cell g rowth i nh i b i t i on by the

Mad/Max complex thro ug h recr ui tment of h i stone deacetylase act i v i ty. C u rr

B i ol 1997;7:357–365.

47.L i J,L i n Q,Wan g W,Wade P,Won g J. Spec i f i c tar g et i n g and const i t u t i ve asso-

c i at i on of h i stone deacetylase complexes

d u r i n g transcr i pt i onal repress i on.

Genes Dev 2002;16:687–692.

https://www.360docs.net/doc/f03961292.html, gg er G,Doetzlhofer A,Sch u etten g r u ber B,et al. The t u mor s u ppressor p53

and h i stone deacetylase 1 are anta g on i st i c re gu lators of the cycl i n-dependent k i nase i nh i b i tor p21/WAF1/CI P1 g ene. Mol Cell B i ol 2003;23:2669–2679.

Chapter 1 /HDAC119 49.Lev i ne AJ. p53,the cell u lar g atekeeper for g rowth and d i v i s i on. Cell

1997;88:323–331.

50.Ko u tsodont i s G,Tentes I,P apakosta P,Mo u stakas A,Kardass i s D. Sp1 plays a

cr i t i cal role i n the transcr i pt i onal act i vat i on of the h u man cycl i n-dependent k i nase i nh i b i tor p21(WAF1/C i p1) g ene by the p53 t u mor s u ppressor prote i n.

J B i ol Chem 2001;276:29,116–29,125.

51.G ui CY,N g o L,X u WS,R i chon VM,Marks P A. H i stone deacetylase (HDAC)

i nh i b i tor act i vat i on of p21WAF1 i nvolves chan g es i n promoter-assoc i ated pro-

te i ns,i ncl u d i n g HDAC1.P roc Natl Acad Sc i U S A 2004;101:1241–1246. 52.Brooks CL,G u W. Ub i q ui t i nat i on,phosphorylat i on and acetylat i on:the molec-

u lar bas i s for p53 re gu lat i on. C u rr Op i n Cell B i ol 2003;15:164–171.

53.Ito A,Kawa gu ch i Y,La i CH,et al. MDM2-HDAC1-med i ated deacetylat i on of

p53 i s req ui red for i ts de g radat i on. EMBO J 2002;21:6236–6245.

54.L u o J,L i M,Tan g Y,Laszkowska M,Roeder RG,G u W. Acetylat i on of p53

a ug ments i ts s i te-spec i f i c DNA

b i nd i n g both i n v i tro and i n v i vo.P ro

c Natl Acad

Sc i U S A 2004;101:2259–2264.

55.P r i valsky ML. The role of corepressors i n transcr i pt i onal re gu lat i on by n u clear

hormone receptors. Ann u Rev P hys i ol 2004;66:315–360.

56.Maz u mdar A,Wan g RA,M i shra SK,et al. Transcr i pt i onal repress i on of oestro-

g en receptor by metastas i s-assoc i ated prote i n 1 corepressor. Nat Cell B i ol

2001;3:30–37.

57.We i LN,H u X,Chandra D,Seto E,Farooq ui M. Receptor-i nteract i n g prote i n

140 d i rectly recr ui ts h i stone deacetylases for g ene s i lenc i n g. J B i ol Chem 2000;275:40,782–40,787.

58.K u rtev V,Mar gu eron R,Kroboth K,O g r i s E,Cava i lles V,Se i ser C.

Transcr i pt i onal re gu lat i on by the repressor of estro g en receptor act i v i ty v i a recr ui tment of h i stone deacetylases. J B i ol Chem 2004;279:24,834–24,843. 59.Kawa i H,L i H,Avraham S,J i an g S,Avraham HK. Overexpress i on of h i stone

deacetylase HDAC1 mod u lates breast cancer pro g ress i on by ne g at i ve re gu lat i on of estro g en receptor alpha. Int J Cancer 2003;107:353–358.

60.Mal A,St u rn i olo M,Sch i ltz RL,Ghosh MK,Harter ML. A role for h i stone

deacetylase HDAC1 i n mod u lat i n g the transcr i pt i onal act i v i ty of MyoD:i nh i b i-t i on of the myo g en i c pro g ram. EMBO J 2001;20:1739–1753.

61.Pu r i P L,Iezz i S,St i e g ler P,et al. Class I h i stone deacetylases seq u ent i ally

i nteract w i th MyoD and pRb d u r i n g skeletal myo g enes i s. Mol Cell 2001;8:

885–897.

62.Mal A,Harter ML. MyoD i s f u nct i onally l i nked to the s i lenc i n g of a m u scle-

spec i f i c re gu latory g ene pr i or to skeletal myo g enes i s.P roc Natl Acad Sc i U S A 2003;100:1735–1739.

63.To u L,L iu Q,Sh i vdasan i RA. Re gu lat i on of mammal i an ep i thel i al d i fferent i a-

t i on and i ntest i ne development by class I h i stone deacetylases. Mol Cell B i ol 2004;24:3132–3139.

64.Ma g a G,H u bscher U.P rol i ferat i n g cell n u clear ant ig en (P CNA):a dancer w i th

many partners. J Cell Sc i 2003;116:3051–3060.

65.Tsa i SC,Valkov N,Yan g WM,G u mp J,S u ll i van D,Seto E. H i stone deacetylase

i nteracts d i rectly w i th DNA topo i somerase II. Nat Genet 2000;26:349–353.

66.Johnson CA,P ad g et K,A u st i n CA,T u rner BM. Deacetylase act i v i ty assoc i ates

w i th topo i somerase II and i s necessary for etopos i de-i nd u ced apoptos i s. J B i ol Chem 2001;276:4539–4542.

67.A u st i n CA,Marsh KL.E u karyot i c DNA topo i somerase II beta.B i oessays

1998;20:215–226.

20Meunier and Seiser 68.Ca i RL,Yan-Neale Y,C u eto MA,X u H,Cohen D. HDAC1,a h i stone deacety-

lase,forms a complex w i th H u s1 and Rad9,two G2/M checkpo i nt Rad prote i ns.

J B i ol Chem 2000;275:27,909–27,916.

69.Cra ig JM,Earle E,Canham P,Won g LH,Anderson M,Choo KH. Analys i s of

mammal i an prote i ns i nvolved i n chromat i n mod i f i cat i on reveals new metaphase centromer i c prote i ns and d i st i nct chromosomal d i str i b u t i on patterns. H u m Mol Genet 2003;12:3109–3121.

70.D u tertre S,Descamps S,P r ig ent C. On the role of a u rora-A i n centrosome f u nc-

t i on. Onco g ene 2002;21:6175–6183.

71.Saka i H,Urano T,Ookata K,et al. MBD3 and HDAC1,two components of

the N u RD complex,are local i zed at A u rora-A-pos i t i ve centrosomes i n M phase. J B i ol Chem 2002;277:48,714–48,723.

72.Dav i d G,T u rner GM,Yao Y,P rotopopov A,De Pi nho RA. mS i n3-assoc i ated

prote i n,mSds3,i s essent i al for per i centr i c heterochromat i n format i on and chro-mosome se g re g at i on i n mammal i an cells. Genes Dev 2003;17:2396–2405. 73.S i mone C,St i e g ler P,Forcales SV,et al. Deacetylase recr ui tment by the C/H3

doma i n of the acetyltransferase p300. Onco g ene 2004;23:2177–2187.

74.Va u te O,N i colas E,Vandel L,Tro u che D. F u nct i onal and phys i cal i nteract i on

between the h i stone methyl transferase S u v39H1 and h i stone deacetylases.

N u cle i c Ac i ds Res 2002;30:475–481.

75.Otte A P,Kwaks TH. Gene repress i on by P olycomb g ro u p prote i n complexes:a

d i st i nct complex for every occas i on? C u rr Op i n Genet Dev 2003;13:448–454.

76.Cao R,Zhan g Y. The f u nct i ons of E(Z)/EZH2-med i ated methylat i on of lys i ne

27 i n h i stone H3. C u rr Op i n Genet Dev 2004;14:155–164.

76a.Sh i YJ,Matson C,Lan F,Iwase S,Baba T,Sh i Y. Re gu lat i on of LSD1 h i stone demethylase act i v i ty by i ts assoc i ated factors. Mol Cell 2005;19:857–864.

76b.Lee MG,Wynder C,Cooch N,Sh i ekhattar R. An essent i al role for CoREST i n n u cleosomal h i stone 3 lys i ne 4 demethylat i on. Nat u re 2005;437:432–435.

77.Dobosy JR,Selker EU. Emer gi n g connect i ons between DNA methylat i on and

h i stone acetylat i on. Cell Mol L i fe Sc i 2001;58:721–727.

78.F u ks F,B u r g ers W A,Brehm A,H ug hes-Dav i es L,Ko u zar i des T. DNA methyltrans-

ferase Dnmt1 assoc i ates w i th h i stone deacetylase act i v i ty. Nat Genet 2000;24:88–91.

79.Robertson KD,A i t-S i-Al i S,Yokoch i T,Wade P A,Jones P L,Wolffe A P. DNMT1

forms a complex w i th Rb,E2F1 and HDAC1 and represses transcr i pt i on from E2F-respons i ve promoters. Nat Genet 2000;25:338–342.

80.F u ks F,B u r g ers W A,God i n N,Kasa i M,Ko u zar i des T. Dnmt3a b i nds deacety-

lases and i s recr ui ted by a seq u ence-spec i f i c repressor to s i lence transcr i pt i on.

EMBO J 2001;20:2536–2544.

81.Ge i man TM,Sankpal UT,Robertson AK,Zhao Y,Zhao Y,Robertson KD.

DNMT3B i nteracts w i th hSNF2H chromat i n remodel i n g enzyme,HDACs 1 and 2,and components of the h i stone methylat i on system. B i ochem B i ophys Res Comm u n 2004;318:544–555.

82.Depl u s R,Brenner C,B u r g ers W A,et al. Dnmt3L i s a transcr i pt i onal repressor

that recr ui ts h i stone deacetylase. N u cle i c Ac i ds Res 2002;30:3831–3838.

83.Gwack Y,By u n H,Hwan g S,L i m C,Choe J. CREB-b i nd i n g prote i n and h i stone

deacetylase re gu late the transcr i pt i onal act i v i ty of Kapos i’s sarcoma-assoc i ated herpesv i r u s open read i n g frame 50. J V i rol 2001;75:1909–1917.

84.L u F,Zho u J,W i edmer A,Madden K,Y u an Y,L i eberman P M. Chromat i n remod-

el i n g of the Kapos i’s sarcoma-assoc i ated herpesv i r u s ORF50 promoter corre-lates w i th react i vat i on from latency. J V i rol 2003;77:11,425–11,435.

Chapter 1 /HDAC121 85.Ch i occa S,K u rtev V,Colombo R,et al. H i stone deacetylase 1 i nact i vat i on by an

adenov i r u s early g ene prod u ct. C u rr B i ol 2002;12:594–598.

86.Zhan g Y,Jones C. The bov i ne herpesv i r u s 1 i mmed i ate-early prote i n (bIC P0)

assoc i ates w i th h i stone deacetylase 1 to act i vate transcr i pt i on. J V i rol 2001;75: 9571–9578.

87.Shestakova E,Band u MT,Doly J,Bonnefoy E. Inh i b i t i on of h i stone deacetyla-

t i on i nd u ces const i t u t i ve derepress i on of the beta i nterferon promoter and con-fers ant i v i ral act i v i ty. J V i rol 2001;75:3444–3452.

87a.Lehrman G,Ho gu e IB,P almer S,et al. Deplet i on of latent HIV-1 i nfect i on i n v i vo:a proof-of-concept st u dy. Lancet 2005;366:549–555.

88.Mannerv i k M,Lev i ne M. The Rpd3 h i stone deacetylase i s req ui red for se g men-

tat i on of the D ro s o phila embryo.P roc Natl Acad Sc i U S A 1999;96:6797–6801.

89.Sh i Y,Mello C. A CB P/p300 homolo g spec i f i es m u lt i ple d i fferent i at i on path-

ways i n Ca e n or ha b ditis e l e gans. Genes Dev 1998;12:943–955.

90.D u fo u rcq P,V i ctor M,Gay F,Calvo D,Hod g k i n J,Sh i Y. F u nct i onal req ui re-

ment for h i stone deacetylase 1 i n Ca e n or ha b ditis e l e gans g onado g enes i s. Mol Cell B i ol 2002;22:3024–3034.

91.Goll i n g G,Amsterdam A,S u n Z,et al. Insert i onal m u ta g enes i s i n zebraf i sh rap-

i dly i dent i f i es g enes essent i al for early vertebrate development. Nat Genet 2002;

31:135–140.

92.Marks P,R i fk i nd RA,R i chon VM,Breslow R,M i ller T,Kelly WK. H i stone

deacetylases and cancer:ca u ses and therap i es. Nat Rev Cancer 2001;1: 194–202.

93.Kelly WK,O’Connor OA,Marks P A. H i stone deacetylase i nh i b i tors:from tar-

g et to cl i n i cal tr i als. Expert Op i n Invest ig Dr ug s 2002;11:1696–1713.

94.Marks P A,M i ller T,R i chon VM. H i stone deacetylases. C u rr Op i n P harmacol

2003;3:344–351.

95.Cho i JH,Kwon HJ,Yoon BI,et al. Express i on prof i le of h i stone deacetylase 1 i n

g astr i c cancer t i ss u es. Jpn J Cancer Res 2001;92:1300–1304.

96.P atra SK,P atra A,Dah i ya R. H i stone deacetylase and DNA methyltransferase

i n h u man prostate cancer.B i ochem B i ophys Res Comm u n 2001;287:

705–713.

97.Halk i do u K,Ga ug han L,Cook S,Le u n g HY,Neal DE,Robson CN. Upre gu lat i on

and n u clear recr ui tment of HDAC1 i n hormone refractory prostate cancer.

P rostate 2004;59:177–189.

98.K i m JH,Cho i YK,Kwon HJ,Yan g HK,Cho i JH,K i m DY. Downre gu lat i on of

g elsol i n and ret i no i c ac i d receptor beta express i on i n g astr i c cancer t i ss u es

thro ug h h i stone deacetylase 1. J Gastroenterol Hepatol 2004;19:218–224.

99.Glaser KB,L i J,Staver MJ,We i RQ,Albert DH,Dav i dsen SK. Role of class I

and class II h i stone deacetylases i n carc i noma cells u s i n g s i RNA. B i ochem

B i ophys Res Comm u n 2003;310:529–536.

100.Zho u Q,Melko u m i an ZK,L u ckton g A,Mon i wa M,Dav i e JR,Strobl JS. Rap i d

i nd u ct i on of h i stone hyperacetylat i on and cell u lar d i fferent i at i on i n h u man breast

t u mor cell l i nes follow i n g de g radat i on of h i stone deacetylase-1. J B i ol Chem 2000;275:35,256–35,263.

101.Fanc iu ll i M,Br u no T,D i P adova M,et al. Ident i f i cat i on of a novel partner of RNA polymerase II s u b u n i t 11,Che-1,wh i ch i nteracts w i th and affects the

g rowth s u ppress i on f u nct i on of Rb. FASEB J 2000;14:904–912.

102.Br u no T,De An g el i s R,De N i cola F,et al. Che-1 affects cell g rowth by i nterfer-

i n g w i th the recr ui tment of HDAC1 by Rb. Cancer Cell 2002;2:387–399.

22Meunier and Seiser 103.D i P adova M,Br u no T,De N i cola F,et al. Che-1 arrests h u man colon carc i noma cell prol i ferat i on by d i splac i n g HDAC1 from the p21WAF1/CI P1 promoter.

J B i ol Chem 2003;278:36,496–36,504.

104.K i m MS,Kwon HJ,Lee YM,et al. H i stone deacetylases i nd u ce an gi o g enes i s by ne g at i ve re gu lat i on of t u mor s u ppressor g enes. Nat Med 2001;7:437–443. 105.N u s i nzon I,Horvath CM. Interferon-st i m u lated transcr i pt i on and i nnate ant i v i ral

i mm u n i ty req ui re deacetylase act i v i ty and h i stone deacetylase 1.P roc Natl Acad

Sc i U S A 2003;100:14,742–14,747.

106.Klampfer L,H u an g J,Swaby LA,A ug enl i cht L. Req ui rement of h i stone deacty-lase act i v i ty for s ig nal i n g by STAT1. J B i ol Chem 2004;279:30,358–30,368. 107.H u E,D u l E,S u n g CM,et al. Ident i f i cat i on of novel i soform-select i ve i nh i b i tors w i th i n class I h i stone deacetylases. J P harmacol Exp Ther 2003;307:720–728.