HDAC3: Taking the SMRT-N-Correct Road to Repression

Home , ETV6, GPS2 (gene), HDAC3, Jun dimerization protein, Mad1

P Karagianni and J Wong1

Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

Known histone deacetylases (HDACs) are divided into repression when targeted to promoters, as well as different classes, and HDAC3 belongs to Class I. Through physical association with the DNA-binding factor forming multiprotein complexes with the corepressors YY1 (Yang et al., 1997; Dangond et al., 1998; Emiliani SMRT and N-CoR, HDAC3 regulates the transcription et al., 1998). Together, these ﬁndings suggested that this of a plethora of genes. A growing list of nonhistone ubiquitously expressed protein could be involved in the substrates extends the role of HDAC3 beyond transcrip- regulation of mammalian gene expression. On the other tional repression. Here, we review data on the composi- hand, HDAC3 contains an intriguingly variable C tion, regulation and mechanism of action of the SMRT/ terminus, with no apparent similarity with other N-CoR-HDAC3 complexes and provide several examples HDACs. This observation led to the hypothesis that of nontranscriptional functions, to illustrate the wide HDAC3 may have some unique properties and may variety of physiological processes affected by this deacety- not be completely redundant with the other HDACs lase. Furthermore, we discuss the implication of HDAC3 (Yang et al., 1997). This is also suggested by the in cancer, focusing on leukemia. We conclude with some differential localization of HDAC3, which, unlike the thoughts about the potential therapeutic efﬁcacies of predominantly nuclear HDACs 1 and 2, can be found in HDAC3 activity modulation. the nucleus, the cytoplasm and at the plasma membrane Oncogene (2007) 26, 5439–5449; doi:10.1038/sj.onc.1210612 (Takami and Nakayama, 2000; Longworth and Laimins, 2006). Detailed domain analysis has revealed Keywords: HDAC3; SMRT; N-CoR; corepressor complex; that the protein contains both nuclear import and histone deacetylation; repression and cancer export signals, which account for this distinct localization pattern (Yang et al., 2002). The subcellular distribution of HDAC3 agrees with its nuclear function and opens up a whole new world of potential Introduction cytoplasmic substrates and regulators.

Initially cloned based on sequence similarity with the previously identified histone deacetylases (HDACs) 1 HDAC3 complexes and 2, HDAC3 was the third mammalian deacetylase to be identified (Yang et al., 1997; Dangond et al., 1998; Composition Emiliani et al., 1998). Its open reading frame predicted a A breakthrough in the understanding of the biological 428 aa protein, with an estimated molecular mass of role of HDAC3 came with the realization that the 49 kDa. Human HDAC3 is 53% identical with human enzyme forms a stable complex with nuclear receptor HDAC1 and 52% identical with human HDAC2 at the corepressor (N-CoR) and silencing mediator of retinoic amino acid level (Yang et al., 1997; Dangond et al., and thyroid receptors (SMRT). Biochemical purifica- 1998). This similarity led to the classification of the tions of both N-CoR/SMRT as well as HDAC3- above three proteins into one family. HDAC8 would be associated proteins, mostly based on immunoaffinity later added to this class, which includes mammalian precipitation followed by mass spectrometry, converged enzymes related to yeast Rpd3 (Buggy et al., 2000). to this conclusion (Guenther et al., 2000; Wen et al., Similar to HDACs 1 and 2, HDAC3 is also ubiquitously 2000; Li et al., 2000; Zhang et al., 2002; Yoon et al., expressed. As expected by the sequence identity, early 2003). At least in HeLa cells, the majority of cellular functional analysis of the HDAC3 protein revealed HDAC3 is found to associate with SMRT and N-CoR common features with HDACs 1 and 2, namely complexes. Both N-CoR and SMRT had been discov- deacetylation of histone substrates, transcriptional ered as interacting partners of unliganded TR and RAR and mediators of their repressive functions (Chen and Correspondence: Dr J Wong, Department of Molecular and Cellular Evans, 1995; Horlein et al., 1995). The two corepressors Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX are high-molecular-weight proteins (B270 kDa), very 77030, USA. similar at the amino acid level, containing nuclear E-mail: [email protected] 1Current address: Institute of Biomedical Sciences, College of Life receptor-interacting domains as well as multiple repres- Science, East China Normal University, Dongchuan Road 500, sor domains (Chen and Evans, 1995; Horlein et al., Shanghai 200241, China. 1995; Ordentlich et al., 1999; Park et al., 1999). Role of HDAC3 in cancer therapy P Karagianni and J Wong 5440 Although N-CoR and SMRT share many functions, context-specific fashion, the consensus favors a stable they are likely not completely redundant, as suggested core N-CoR/SMRT complex comprising HDAC3, N- by the lethality of N-CoR deficient mice (Jepsen et al., CoR/SMRT, TBL1/TBLR1 and GPS-2. It is note- 2000). Identification of HDAC3 as the catalytic worthy that the core complex of SMRT and N-CoR component of the N-CoR/SMRT complexes provided containing HDAC3, TBL1, TBLR1 and GPS2 is very a mechanistic link between transcriptional repression stable, resistant to high concentration of salt and and histone deacetylation. Via their interactions with a detergents (Zhang et al., 2002). Furthermore, the number of different transcription factors, the two association of HDAC3 with N-CoR/SMRT is evolutio- corepressors recruit HDAC3 to specific promoters, narily conserved, as the yeast SET3 complex is believed where the enzyme deacetylates histones and mediates to be orthologous to the mammalian N-CoR/SMRT silencing of the corresponding genes. complexes (Pijnappel et al., 2001). The purified N-CoR/SMRT complexes contain additional components including transducin b-like 1 (TBL1) Substrate specificity (Guenther et al., 2000; Li et al., 2000), the TBL1-related The existence of different HDACs and HDAC complexes protein (TBLR1) (Zhang et al., 2002; Yoon et al., 2003), raises the question of potential specificity in their and G protein pathway suppressor 2 (GPS-2) (Zhang enzymatic activities and general functions. Early studies et al., 2002; Yoon et al., 2003). Both TBL1 and TBLR1 showed that, like HDAC1 and HDAC2, HDAC3 isolated interact directly with SMRT and N-CoR but not with from mammalian cells can deacetylate both H3 and H4 in HDAC3 (Guenther et al., 2000; Zhang et al., 2002; Yoon free histones or nucleosome substrates (Yang et al., 1997; et al., 2003). In contrast to SMRT and N-CoR, TBL1 Dangond et al., 1998; Emiliani et al., 1998). In a more and TBLR1 are not required for HDAC3 enzymatic detailed study, Johnson et al. (2002) immunoprecipitated activity (Guenther et al., 2000; Zhang et al., 2002). HDAC1, -2, -3 and -6 from cell extracts and compared Although their functions may be at least partially their kinetics of cleavage of the acetyl group on different redundant, TBL1 and TBLR1 are essential for transcrip- lysine residues of hyperacetylated free histones. Although tional repression mediated by TR and other transcription this approach does not provide pure enzymatic prepara- factors (Guenther et al., 2000; Yoon et al., 2003). Work tions, some differences in the preferred lysine residues of by Perissi et al. (2004) further indicates that TBL1 and the individual complexes were observed. The in vitro TBLR1 are critical for transcriptional activation by a results suggested that HDAC3 could completely deacety- number of different nuclear receptors examined. Accord- late H2A, H4K5Ac and H4K12Ac, but only partially ing to the proposed model, in addition to their repressive deacetylate H3, H2B, H4K8Ac and H4K16Ac (Johnson function, TBL1 and TBLR1 also mediate proteasome- et al., 2002). Compared with HDAC1, HDAC3 deacety- dependent degradation of SMRT/N-CoR complexes lated H4K8Ac, H4K16Ac and H2B at the same rate, but from promoters, to allow for de-repression and subse- it deacetylated H4K5Ac, H4K12Ac and H2AK5Ac much quent recruitment of coactivators. Thus, the two proteins more rapidly. become essential for gene expression. However, Yoon Looking at an endogenous retinoic acid-regulated et al. (2005) failed to observe any effect of TBL1/TBLR1 gene, Hartman et al. (2005) observed a similar specificity in transcriptional activation, leaving the exact roles of of the N-CoR/SMRT-HDAC3 complex. Upon ligand TBL1/TBLR1 controversial. removal, recruitment of the corepressor complex re-estab- Human GPS2 was initially identified via its ability to lishes the repressed state of the gene and this involves suppress lethal G protein subunit-activating mutations progressive deacetylation of lysines in H4 tails. Deacety- in the yeast pheromone response pathway (Spain et al., lation of the H4 lysines occurs in a nonrandom pattern, 1996). Overexpression of GPS2 in mammalian cells has starting with K5 and followed by K8, K12 and K16, been shown to potently suppress JNK1 activation by and this ordered process is dependent on the activity of serum factors or TNFa (Spain et al., 1996; Jin et al., HDAC3 (Hartman et al., 2005). 1997) and promote the transactivation activities of Using an in vitro reconstituted chromatin template, bovine papillomavirus E2 and tumor suppressor p53 Vermeulen et al. (2004) tested histone deacetylation proteins (Breiding et al., 1997; Peng et al., 2001). Within specificity of SMRT/N-CoR complexes. When targeted the N-CoR complex, GPS-2 interacts directly with to preacetylated nucleosomal templates, Sin3/HDAC N-CoR and TBL1 and may aid the assembly and was found to deacetylate both H3 and H4, whereas the stabilization of the complex (Zhang et al., 2002). N-CoR/SMRT-HDAC3 complex displayed preferential Importantly, the association with N-CoR/HDAC3 is activity toward H3 (Vermeulen et al., 2004). This result required for GPS-2 to inhibit the JNK pathway (Zhang is somewhat surprising, considering the data discussed et al., 2002). Therefore, these results suggest a role of the above (Johnson et al., 2002; Hartman et al., 2005). N-CoR/HDAC3 complex in the orchestration of gene Future work is necessary to reconcile this difference. expression upon various extracellular signals. Other HDACs (1, 2, 4, 5, 7 and 9) and Sin3 have been reported to interact with N-CoR/SMRT based A feed-forward mechanism of repression by SMRT/ on different complex purification conditions or interac- N-CoR-HDAC3 complexes tion assays (Alland et al., 1997; Heinzel et al., 1997; An emerging theme from several studies on the Nagy et al., 1997; Huang et al., 2000; Kao et al., recruitment of SMRT/N-CoR-HDAC3 complexes to 2000). Although these interactions could occur in a chromatin templates is that histone deacetylation plays a

Oncogene Role of HDAC3 in cancer therapy P Karagianni and J Wong 5441 positive feed-forward role in this process. Both SMRT (DAD) includes one of the two closely spaced SANT and N-CoR as well as TBL1 and TBLR1 have been motifs in the N terminus of SMRT and N-CoR. shown to bind preferentially hypoacetylated H4 tail Interestingly, the second SANT motif is part of a (Yoon et al., 2003; Hartman et al., 2005). Similarly, histone-interacting domain and functions synergistically SMRT/N-CoR-HDAC3 complexes were shown to bind with the DAD to promote histone deacetylation (Yu et al., to hypoacetylated chromatin template in vitro, although 2003). The DAD of N-CoR/SMRT binds both the amino- in this case deacetylated H3 rather than H4 appeared to and carboxy- termini of HDAC3 (Guenther et al., 2001) be important (Vermeulen et al., 2006). Taken together, and forms a unique four-helical structure (Codina et al., these results illustrate a working model (Figure 1) in 2005). The requirement for an intricately folded HDAC3 which the enzymatic product of the deacetylase becomes surface for interaction with the corepressors might allow a favorable binding substrate for N-CoR/SMRT com- for better regulation of its activity and prevent ectopic plexes, thereby stabilizing and propagating the repres- functions. The necessity for such fine control is also sive function of the complex (Hartman et al., 2005; illustrated by the fact that active SMRT-HDAC3 complex Yoon et al., 2005; Vermeulen et al., 2006). Further formation can occur only after presentation of properly evidence suggests that this feed-forward mechanism folded HDAC3 to SMRT by chaperones, such as the could also apply to Sin3/HDAC1/2 mediated repression TCP-1 ring complex, in an ATP-dependent process, (Yoon et al., 2005; Vermeulen et al., 2006). termed ‘priming’ (Guenther et al., 2002). More recently, the enzymatic activity of HDAC3 has also been shown to be regulated by phosphorylation/ Regulation of HDAC3 activity dephosphorylation. Ser424 of HDAC3 could be phos- phorylated by CK2 and dephosphorylated by protein The role of SMRT/N-CoR extends beyond the recruit- serine/threonine phosphatase 4 (Zhang et al., 2005b). ment of HDAC3 to specific chromatin loci, since their The latter copurifies with the N-CoR complex and interaction with HDAC3 strongly potentiates HDAC3 interacts with the N terminus of HDAC3 (Zhang et al., enzymatic activity (Wen et al., 2000; Guenther et al., 2001; 2005b). Ser424 phosphorylation on HDAC3 was shown Zhang et al., 2002). Guenther et al. (2001) mapped a to stimulate its HDAC activity. A similar effect was later domain highly conserved between N-CoR and SMRT, proposed for phosphorylation of HDAC3 mediated required for interaction with HDAC3 and activation of its by the DNA-dependent protein kinase (DNA-PK, catalytic function. This deacetylase activating domain Jeyakumar et al., 2007). Interestingly, HDAC3 also

-CoR SMRT/N L1 GPS2 TB T/N-CoR HDAC3 TBLR1 SMR L1 GPS2 TB HDAC3 TBLR1

TF Ac

TF Ac Ac Ac Ac Ac Ac Ac

Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac Ac

H H

D D A A C C S S 3 3 M M G R G P R P T S T S 2 / / 2 N N T T T - T B - C B B C B L L L o L R o 1 R R R 1 TF 1 1 TF Ac Ac

Ac Ac Ac Ac Ac Ac Ac Figure 1 A feed-forward model illustrating how histone deacetylation contributes to recruitment and transcriptional repression by SMRT/N-CoR-HDAC3 complexes. The recruitment of the corepressor complexes is initiated via protein–protein interaction between a sequence specific transcription factor such as TR/RXR heterodimers and a component (SMRT/N-CoR) of the complex. This interaction enriches the corepressor complexes to the specific region and initiates histone deacetylation through associated histone deacetylases-3 (HDAC3). Histone deacetylation generates hypoacetylated histone tails that are the preferential binding sites for SMRT/N-CoR and/or TBL1/TBLR1. The binding of SMRT/N-CoR and/or TBL1/TBLR1 to hypoacetylated histone tails in turn stabilizes the recruitment of SMRT/N-CoR complexes and leads to further deacetylation and finally transcriptional repression. Ac, acetylation; SMRT, silencing mediator of retinoic and thyroid receptors; N-CoR, nuclear receptor corepressor; TBL1, transducin beta like 1; TBLR1, TBL1-related protein. Modified from Figure 7 in Yoon et al., Mol Cell Biol 25(1):324–335.

Oncogene Role of HDAC3 in cancer therapy P Karagianni and J Wong 5442 localizes to the cellular membrane and is a substrate for differentiation, proliferation and apoptosis (Jepsen and Src, a membrane associated tyrosine kinase, suggesting a Rosenfeld, 2002). At an organismal level, they play potential role of HDAC3 in cytoplasmic signal trans- critical role in development, metabolism and inflamma- duction (Longworth and Laimins, 2006). Furthermore, tion. Their physiological function is thought to be HDAC3 activity can also be regulated indirectly largely mediated through their ability to facilitate through phosphorylation of its associated proteins. For transcriptional repression by a number of different instance, IKKa-mediated phosphorylation of RelA/p65 transcription factors. Histone deacetylation is thought and SMRT on nuclear factor-kB (NF-kB)-regulated to repress gene expression by at least two different promoters results in disruption of the complex and mechanisms. First, removal of the acetyl group increases subsequent de-repression of the corresponding genes the local positive charge of histones, increasing their (Hoberg et al., 2006). affinity for the negatively charged DNA. This generates In addition to protein–protein interactions and phos- a tight chromatin structure, refractory to transcription. phorylation, subcellular localization may serve as another Moreover, deacetylation reduces the affinity of bromo- regulatory mechanism for HDAC3. For example, export domain-containing coactivators (Zeng and Zhou, 2002). of the N-CoR complex to the cytoplasm in response to In this general way, the N-CoR/SMRT complex interleukin (IL)-1b stimulation has been proposed as a mediates repression of unliganded nuclear receptors, mechanism of de-repression of a set of NF-kB regulated such as TR, RAR, RXR, PPAR and orphan nuclear genes (Baek et al., 2002). This regulation is mediated by receptors, such as Rev-Erb, COUP-TFs, and DAX1 TAB2, a known activator of the NF-kB pathway (Takaesu (Shibata et al., 1997; Zamir et al., 1997; Crawford et al., et al., 2000; Baek et al., 2002). The reverse process, nuclear 1998; Jepsen and Rosenfeld, 2002; Yin and Lazar, 2005). translocation of HDAC3, has been described as a mecha- Generally, an unliganded receptor associates with nism of inhibition of PPARg by TNFa (Gao et al., 2006). N-CoR/SMRT, but this interaction is lost as a result Cytoplasmic HDAC3 was shown to associate with IkBa- of the receptor conformational change upon ligand and TNFa-treatment induced degradation of the latter binding. Sometimes, repression occurs independently of and HDAC3 release, allowing it to enter the nucleus and the presence or absence of ligand. For instance, cyclin repress the activity of PPARg (Gao et al., 2006). D1 can repress both basal as well as ligand-dependent Recently, subcellular localization of HDAC3 was also functions of TR and PPARg, by recruiting HDAC3 (Lin shown to be controlled by caspase-dependent cleavage et al., 2002; Fu et al., 2005). In other examples, it is the during apoptosis (Escaffit et al., 2007). Removal of the antagonist-bound receptor that interacts with N-CoR/ C-terminal part of HDAC3, which is required for SMRT to repress transcription (Jackson et al., 1997; nuclear localization, results in accumulation of the Smith et al., 1997; Lavinsky et al., 1998). In addition to cleaved protein to the cytoplasm. The redistribution of nuclear receptors, other transcription factors, including HDAC3 is required for proapoptotic gene activation Mad, BCL6, Pit1 and ETO also use corepressor and subsequent death of several human cell types complexes to establish and maintain the inactive state (Escaffit et al., 2007). Interestingly, the cleaved HDAC3 of their target genes (Heinzel et al., 1997; Huynh and protein appears to maintain its deacetylase enzymatic Bardwell, 1998; Lutterbach et al., 1998; Wang et al., activity, raising a possible cytoplasmic role for the 1998; Xu et al., 1998). cleaved HDAC3 (Escaffit et al., 2007). Although in some cases repression is a result of However, the question of whether cytoplasmic coordinated function of multiple HDAC complexes, in HDAC3 is enzymatically active still remains open. others, HDAC3 is the preferred enzyme for this task. Theoretically, evolution may have favored a model in For instance, HDAC3 is critically important for TR- which the enzyme is inactive in the cytoplasm. This mediated repression (Ishizuka and Lazar, 2003; Yoon would prevent aberrant functions of this key regulatory et al., 2005). Li et al. (2002) have shown that unliganded protein in the cytoplasm. However, HDAC3 might also TR recruits only N-CoR and SMRT/HDAC3 com- have cytoplasmic functions. As discussed next, several plexes for repression, whereas another transcription nonhistone proteins including cytoplasmic proteins have factor, Mad1, recruits only the Sin3/HDAC1/2 deace- been shown to be deacetylated by this enzyme. Given tylase complex. Interestingly, in addition to their effect that proper association with N-CoR/SMRT is required on covalent histone modifications, N-CoR and HDAC3 for the enzyme to be functional toward histones (Wen are also required for recruitment of the SNF2Hchromatin et al., 2000; Guenther et al., 2001; Zhang et al., 2002), an remodeller to facilitate unliganded TR-mediated intriguing question is whether a similar mechanism repression (Alenghat et al., 2006). might also be required for an active cytoplasmic But even in cases where multiple complexes are HDAC3 and/or toward nonhistone substrates. required for repression, their roles do not seem to be redundant, as suggested by work on tamoxifen-bound ER (Liu and Bagchi, 2004). Examining the recruitment Diverse biological functions of HDAC3 of different factors on endogenous promoters, it was observed that both N-CoR/HDAC3 and the NuRD Repression of transcription through histone complex were recruited by tamoxifen-complexed ER, deacetylation but in a sequential manner, following a strict choreo- HDAC3 and the N-CoR/SMRT complex regulate graphy of events (Liu and Bagchi, 2004). The distinct a wide repertoire of cellular processes, including functions of different HDACs and HDAC complexes

Oncogene Role of HDAC3 in cancer therapy P Karagianni and J Wong 5443 are also suggested by overexpression/downregulation in both cases, HDAC3 was also found to deacetylate the studies as well as developmental profiling of individual responsible acetyltransferases (PCAF and p300/CBP) HDACs in Drosophila (Cho et al., 2005; Foglietti et al., for these proteins (Chuang et al., 2006; Gregoire et al., 2006). Such studies reveal unique sets of genes regulated 2007). Moreover, a subset of N-CoR-HDAC3 complex by each enzyme. Surprisingly, similar numbers of genes copurifies with CBP in HeLa cells and N-CoR can were found to be repressed and activated in each case, interact directly with CBP (Cowger and Torchia, 2006). perhaps through both direct and indirect effects (Cho Deacetylation of the acetyltransferases was shown to et al., 2005; Foglietti et al., 2006). inhibit their function in the above examples. Finally, HDAC3 negatively regulates the activity of transcriptional elongation factor P-TEFb through deacetylation Deacetylation of nonhistone substrates of CDK9 subunit (Fu et al., 2007). We expect that more Acetylation regulates the localization, stability, inter- and more proteins will be identified to be regulated actions and activity of a growing number of nonhist- through deacetylation by HDAC3 or its associated one proteins (Kouzarides, 2000; Glozak et al., 2005). protein complexes. Examples include transcription factors, signaling mole- cules, molecular chaperones and enzymes (Figure 2). By reversing this modification, HDAC3 obtains a critical HDAC3 and the histone code: beyond deacetylation role in various processes. For instance, the NF-kB protein RelA was shown to undergo inducible acetyla- The histone deacetylase activity of the N-CoR/SMRT tion, which renders it a poor-binding substrate for IkB complex ranks it among the key factors in chromatin (Chen et al., 2001). HDAC3 regulates the duration of regulation. However, in addition to the direct effect on NF-kB action by deacetylating RelA and promoting its histone acetylation, the HDAC3-N-CoR complex may interaction with inhibitory-kB(IkB), thus leading to its impact chromatin structure in other ways. For instance, nuclear export, termination of NF-kB signaling, as well a recent study showed that HDAC3 is recruited to the as replenishment of the cytoplasmic pool of RelA-IkB mitotic chromosomes through its interaction with (Chen et al., 2001). HDAC3 also deacetylates SRY, a A-kinase anchor protein 95 (AKAP95) and another master regulator of testis organogenesis, regulating its related protein, homologous to AKAP95 (HA95) (Li subcellular localization and activity (Thevenet et al., et al., 2006). HDAC3-mediated deacetylation of histones 2004). In addition, HDAC3-mediated deacetylation of during mitosis is required for subsequent phosphoryla- p53 upon shear stress appears to be critical for tion of H3 on Ser10 by the aurora kinase B (Li et al., differentiation of stem cells into epithelial cells (Zeng 2006). H3 Ser10 phosphorylation is, in turn, required for et al., 2006). Furthermore, HDAC3 deacetylates myo- HP1 dissociation, proper chromosome condensation cyte enhancer factor 2, a transcription factor important and segregation (Wei et al., 1999; Fischle et al., 2005; for differentiation, apoptosis and survival of different Hirota et al., 2005). This example illustrates a nontran- cell types (Gregoire et al., 2007), as well as glial cell scriptional effect of HDAC3 during mitosis. missing (GCMa), which is important in development An interesting twist to the story of N-CoR/HDAC3- and differentiation (Chuang et al., 2006). Interestingly, mediated repression came with the identification of

Ac p53 Ac p21 p53 SRY differentiation SRY sex determination SMRT/N-CoR Nuclear export

CBP/p300 HDAC3 RelA MEF2 myogenesis Nuclear export Ac NF B signaling NF B RelA I B

CBP/p300 GCM placental morphogenesis

Figure 2 Representative nonhistone substrates of histone deacetylase-3 (HDAC3). In addition to histones, an increasing number of proteins has been shown to be substrates for HDAC3. Deacetylation of these proteins by HDAC3 affects various aspects, ranging from subcellular localization, DNA binding to protein stability.

Oncogene Role of HDAC3 in cancer therapy P Karagianni and J Wong 5444 JMJD2A as an associated protein with the complex promoters of AML1 (renamed RUNX1) target genes (Zhang et al., 2005a). JMJD2A has histone demethylase via their interaction with the TEL moiety of TEL- activity for H3 K9 and K36 (Klose et al., 2006; AML1 (Chakrabarti and Nucifora, 1999; Fenrick et al., Whetstine et al., 2006). Its double tudor domain binds 1999; Guidez et al., 2000). The latter is the fusion methylated H3 K4 and H4 K20 (Huang et al., 2006). protein generated in about one fourth of pediatric B-cell Although only small fraction of JMJD2A is in complex ALL patients, as a result of the t(12;21) translocation with N-CoR (Zhang et al., 2005a), the physical (Romana et al., 1995; Shurtleff et al., 1995). Normally, association of this demethylase with the deacetylase comp- AML1 positively regulates a number of genes required lex may imply functional interplay between the two for hematopoiesis (Okuda et al., 1996; Wang et al., 1996; activities and potential cross-talk between the modifica- Tanaka et al., 1997), whereas repression of these genes tions they catalyse. by TEL-AML1 and its interacting corepressors is thought to contribute to the leukemic phenotype (Frank et al., 1995; Fears et al., 1997; Uchida et al., 1997; HDAC3 and cancer Guidez et al., 2000). Similarly, a common translocation in AML patients, t(8;21) results in the generation of Initial implication of HDAC3 in carcinogenesis was fusion protein AML1 and ETO (eight-twenty-one or based on correlative studies reporting aberrant expres- MTG8), which also recruits corepressors and HDACs sion and/or localization of HDAC3 in various tumors. by the C terminus of ETO, leading to repression of the For instance, increased HDAC3 mRNA and protein AML1 target genes (Rowley, 1982; Erickson et al., 1992; was observed in squamous cell lung carcinomas Gelmetti et al., 1998; Lutterbach et al., 1998; Wang (Bartling et al., 2005) as well as in astrocytic glial et al., 1998; Amann et al., 2001). Analogous effect has tumors (Liby et al., 2006). The latter also display been described for the fusion protein MTG16a-AML1, deregulated, strongly pronounced cytoplasmic HDAC3 resulting from the t(16;21) translocation, present in a protein localization and increased number of mRNA number of AML patients (Gamou et al., 1998; and protein isoforms compared to nonmalignant tissues Hoogeveen et al., 2002). (Liby et al., 2006). Silencing of HDAC3 in colon cancer Acute promyelocytic leukemia (APL) is a subtype of cell lines, which normally express high levels of the AML characterized by excess promyelocytes and protein, resulted in cell growth inhibition, differentiation deficiency in cells of the myeloid lineage. APL is and increased apoptosis (Wilson et al., 2006). These commonly due to translocations affecting the RARa effects were thought to be mediated by regulation of p21 locus (reviewed by Zelent et al., 2001). The most gene (Wilson et al., 2006). At a mechanistic level, common genetic cause of APL is t(15;17), which HDAC3 was shown to be recruited by the tumor antigen rearranges the PML and RAR genes. As a consequence, MAGE-A to impair the transactivation of the tumor a fusion protein between PML and the RARa receptor suppressor p53, thereby conferring chemoresistance is produced and occupies RARE-containing promoters. (Monte et al., 2006). Finally, Narita et al. (2005), based Normal regulation of these promoters depends on on studies with human maxillary carcinoma cells, RARa-mediated repression in the absence of retinoic proposed that inhibition of HDAC3 combined with acid and activation in the presence of ligand. This hyperthermia may provide an efficient therapeutic process is critical for proper differentiation of myeloid approach for cancer. cell lineages. Contrary to full-length RAR, PML-RARa does not respond to physiological RA levels. Therefore, the fusion protein functions as a constitutive repressor HDAC3 in leukemia of the RAR-target genes, blocking differentiation and resulting in leukemogenesis. However, this disease Leukemia is distinguished into different types, depend- responds well to pharmacological levels of all-trans- ing on what blood cell line is affected. The disease can retinoic-acid (ATRA) and patients usually achieve also be acute or chronic. Acute leukemia accounts for complete remission after treatment (Huang et al., about one-third of all childhood cancers and is 1988). This treatment restores normal granulocyte categorized to acute lymphoblastic (ALL) and acute differentiation and provides a paradigm of differentia- myeloid (AML). A recurrent theme in this disease is a tion cancer therapy. Atsumi et al. (2006) showed that the reciprocal and balanced chromosomal rearrangement N-CoR/HDAC3 complex is involved in this constitutive that generates an oncogenic fusion protein. The repression in PML-RARa-expressing cells and that oncogenic properties of the fusion protein are usually RNA interference against HDAC3 could activate a result of combination of the DNA-binding domain of expression of the above genes. In addition to promoting one transcription factor with the transcriptional cor- histone deacetylation, HDAC3 has been proposed to aid egulator-interacting domain of another factor. Many of silencing of the PML-RARa targeted genes by recruiting these fusion proteins have been shown to interact with MBD1 (Villa et al., 2006). N-CoR/SMRT corepressors and compelling evidence A different APL-causing translocation, t(11;17), gives shows that aberrant recruitment of the correpressor the PLZF-RARa fusion protein, which functions proteins correlates with the oncogenic activities of the similarly to the PML-RARa protein discussed above, fusion proteins. For instance, N-CoR/SMRT-HDAC3 maintaining repression of critical genes for blood cell and other corepressors are aberrantly recruited to the differentiation (Dong et al., 1996). However, in contrast

Oncogene Role of HDAC3 in cancer therapy P Karagianni and J Wong 5445 to PML-RARa, PLZF-RARa is insensitive to ATRA cloning of HDAC3 from stimulated T cells alluded to (Licht et al., 1995). This is because PLZF-RAR a possible role of this enzyme in cell cycle progression, maintains association with corepressors N-CoR/SMRT further supported by the fact that both overexpression and HDACs, through the PLZF moiety, in an RA- and downregulation of this molecule causes G2/M arrest resistant fashion (Hong et al., 1997; Grignani et al., (Dangond et al., 1998; Wilson et al., 2006). Compared to 1998; Lin et al., 1998). As expected, HDAC activity other HDACs, HDAC3 and HDAC1 downregulation plays a critical role in the pathogenesis of these had more pronounced effect on cancer cell proliferation leukemias and a combination of retinoic acid with (Glaser et al., 2003). Critical roles of HDAC3 in cellular HDAC inhibitors has been proposed as a poten- differentiation have also been described in different tial therapeutic strategy (Grignani et al., 1998; Lin contexts. For instance, HDAC3 enzymatic function is et al., 1998). utilized by Jun dimerization protein 2 (JDP2) to In support of a critical role of SMRT/N-CoR- maintain the c-jun in its inactive state (Jin et al., 2002). HDAC3 in leukemias, Racanicchi et al. (2005) achieved Similarly, HDAC3 is utilized by PPARg to maintain restoration of differentiation in AML1/ETO and PML/ transcriptional repression of its target genes and block RAR-expressing cells by overexpressing specific N-CoR adipogenesis (Fajas et al., 2002) as well as by Runx2, to fragments. By interacting with the fusion proteins, not mediate repression of osteoblast genes (Schroeder et al., only did the overexpressed fragments block their 2004). In contrast, the tumor suppressor Kruppel-like interaction with N-CoR/SMRT, but they also disrupted factor-6 (KLF6) recruits HDAC3 to mediate repression the complex and targeted the fusion protein for of the proto-oncogene d-like 1 (Dlk1), which encodes an degradation (Racanicchi et al., 2005). These findings inhibitor of adipocyte differentiation, thus promoting highlight the importance of understanding the molecular adipogenesis (Li et al., 2005). HDAC3 also represses the basis of the malignancy to design novel therapeutic transcription of the gene encoding the growth-differ- strategies. They also suggest that simultaneous targeting entiation factor 11 (Gdf11), which controls several of multiple pathogenic players may provide a more developmental processes (Zhang et al., 2004). Finally, efficient means of fighting the disease. two recent publications illustrate a more specific implication of HDAC3 in apoptosis. The first study shows that cytoplasmic relocalization of cleaved HDAC3 as an attractive therapeutic target HDAC3 to be critical for cell death (Escaffit et al., 2007), whereas the other demonstrates a transcriptional In the 30-year period following the discovery of effect of HDAC3 on c-jun (Xia et al., 2007). chemical inhibitors of HDACs (Riggs et al., 1977; The above findings indicate that HDAC3 could be a Vidali et al., 1978), such pharmacological compounds suitable target for cancer therapy. Particularly in the have transited from the laboratory bench to the case of leukemia, research generates hope for targeting treatment of cancer patients (reviewed by Johnstone, HDAC3 in the design of novel therapeutic strategies. 2002; Karagiannis and El-Osta, 2007). Although early Understanding the context of HDAC3 function in trials have used broad-spectrum inhibitors, selective different diseases could benefit combinatorial pharma- targeting of specific deacetylases may provide a better cological approaches as well as individualized strategies alternative. based on the unique profile of each patient. Pharmacological treatment of cancer commonly aims to one or more of the following effects: (1) cell cycle Acknowledgements arrest, (2) differentiation and (3) apoptosis of the malignant cells. Evidence illustrates key roles of Research on corepressors carried out in our laboratory was HDAC3 in all three processes. Differential display funded by NIHDK58679.

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