Histone Deacetylases and Cancer
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Oncogene (2007) 26, 5420–5432 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Histone deacetylases and cancer MA Glozak and E Seto H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA Histone deacetylases (HDACs) regulate the expression functions of the enzymes they inhibit. In this review, and activity of numerous proteins involved in both cancer we will address the molecular mechanisms by which initiation and cancer progression. By removal of acetyl HDACs act and how these actions relate to cancer. groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. In addition to histones, HDACs bind to and deacetylate a Chromatin modifications and cancer variety of other protein targets including transcription factors and other abundant cellular proteins implicated in Histones comprise the protein backbone of chromatin. control of cell growth, differentiation and apoptosis. This Histone acetyltransferases (HATs) acetylate the e-amino review provides a comprehensive examination of the tran- group of lysine (K) residues on histones, thereby scriptional and post-translational mechanisms by which neutralizing their positive charge, which diminishes their HDACs alter the expression and function of cancer- ability to bind to negatively charged DNA. In addition, associated proteins and examines the general impact of acetylation of histone H4-K16 specifically disrupts HDAC activity in cancer. the formation of higher-order chromatin structures et al Oncogene (2007) 26, 5420–5432; doi:10.1038/sj.onc.1210610 (Shogren-Knaak ., 2006). An open chromatin configuration provides accessibility for specific tran- Keywords: acetylation; deacetylation; cancer; HDAC; scription factors and the general transcription machin- HDAC inhibitors ery. HDACs remove the acetyl groups, allowing compacted chromatin to reform (Figure 2). Among their many properties, HDACs are required for cell- cycle progression. Indeed, HDAC inhibitors, including NaB, trichostatin A (TSA) and trapoxin, cause mam- malian cells to undergo cell-cycle arrest. Using a Introduction trapoxin affinity column, HDAC1 was purified bio- chemically, subsequently cloned and shown to have During the normal lifecycle, a cell encounters numerous HDAC activity (Taunton et al., 1996). In an unrelated opportunities where it must decide whether to prolifer- series of experiments, HDAC2 was cloned on the basis ate, differentiate or die. A defect in any of these of its interaction with the transcriptional activator/ processes may result in cancer, or the uncontrolled repressor YY1 and was shown to have transcriptional growth of the cell. It has been appreciated for decades repressor activity (Yang et al., 1996). As such, the first that histone deacetylases (HDACs) play an important mammalian HDACs were cloned independently, using role in cancer development since the first observation distinct methods. The same roles that HDACs play in that sodium butyrate (NaB), later identified as an influencing cell-cycle progression and repressing tran- HDAC inhibitor, can cause the morphological reversion scription also have important implications in their of the transformed cell phenotype (Ginsburg et al., 1973; connection to cancer. Altenburg et al., 1976; Boffa et al., 1978). Currently, Since the initial cloning of HDAC1 and HDAC2, at HDAC inhibitors are in clinical trials to treat a variety least 16 additional human HDACs have been identified of malignancies. HDAC inhibitors can block cell and are grouped into four classes: class I comprises proliferation, promote differentiation and induce apop- HDAC1–3 and 8, which show similarity to yeast RPD3; tosis, any of which is desirable to thwart the growth of class II comprises HDAC4–7, 9 and 10, which show rogue cells (Figure 1). Despite decades of research, the similarity to yeast HDA1; class III the NAD þ -depen- precise mechanism(s) by which these inhibitors work dent HDACs, comprises SIRT1–7, which show similar- remains far from clear. In many cases, they may ity to yeast SIR2; class IV comprises HDAC11, which influence multiple targets. To understand how HDAC has some features of both class I and II HDACs inhibitors function, we must first understand the (Gregoretti et al., 2004). Class III HDACs are not affected by the cytostatic HDAC inhibitors, but are Correspondence: Dr E Seto, H. Lee Moffitt Cancer Center & Research inhibited by nicotinamide. Institute, SRB 23011, 12902 Magnolia Drive, Tampa, FL 33612, USA. Histone acetylation and deacetylation does not occur E-mail: ed.seto@moffitt.org in a vacuum. Specific patterns of histone acetylation and HDACs and cancer MA Glozak and E Seto 5421 promoters of genes de-repressed by HDAC inhibitors proliferation differentiation often contain hypermethylated DNA, indicating cross- talk between histone acetylation/methylation and DNA methylation. Each of these events can have profound implications for gene expression in normal and cancer- ous cells. Epigenetic changes, including global DNA hypo- CDKI differentiation factors methylation and promoter CpG island hypermethyla- tion, have long been recognized as characteristics that distinguish cancer cells from their normal counterparts. HDAC HDAC Recently, very specific changes in post-translational modification of histones that characterize cancer cells pro-apoptotic factors have been identified as well. For example, the coupled X loss of acetylation of histone H4-K16 and trimethyla- tion of histone H4-K20 can be considered a common feature of cancer cells as compared to their normal RIP counterparts (Fraga et al., 2005). These changes occur early and accumulate as the cancer progresses. Hypoa- apoptosis cetylation of histone H4-K16 is caused at least in part by diminished recruitment of the MYST (MOZ, Ybf2/Sas3, Sas2 and Tip60) family of HATs (Fraga et al., 2005); proliferation differentiation however, an increase in HDAC recruitment and/or activity cannot be ruled out. Indeed, the class III HDAC SIRT2 shows preference for deacetylation of histone H4-K16. Although this specific deacetylation occurs at the G2/M transition of the cell cycle, it appears to influence the timing of S-phase entry (Vaquero et al., CDKI differentiation factors 2006). In addition to defining cancer cells, specific histone modifications can be used to predict cancer recurrence. Histone H3-K18 acetylation coupled with HDACi HDAC HDAC HDACi histone H3-K4 dimethylation confers lowered risk for prostate cancer recurrence (Seligson et al., 2005). While pro-apoptotic factors these findings presently apply only to prostate cancer, it is likely that similar modifications will be found in other cancer types. In addition, the observation that low RIP acetylation levels correlate with negative outcomes may provide a basis for the clinical use of HDAC inhibitors. apoptosis Figure 1 (a) HDAC-mediated repression of genes can cause uncontrolled cell growth. HDACs repress the transcription of (1) cyclin-dependent kinase inhibitors (CDKI), allowing continued Histone deacetylation: the classic examples proliferation; (2) differentiation factors, allowing proliferation instead of differentiation; (3) proapoptotic factors, permitting Upon the identification and cloning of HDACs, it was survival. (b) HDAC inhibitors (HDACi) can restore appropriate quickly ascertained that HDACs were recruited to gene expression, preventing the uncontrolled growth of the cell. promoters to repress transcription, thereby counter- HDAC, histone deacetylases. acting the activating effects of HATs. In the simplest view, recruitment of HDACs causes decreased histone acetylation that compacts chromatin and precludes deacetylation are typically influenced by other histone access by the transcription machinery, resulting in modifications. Together, these post-translational mod- transcriptional repression (Figure 2). HDACs act on ifications potentially generate a ‘histone code’ (Jenuwein multiprotein complexes and several distinct complexes and Allis, 2001). For example, histone H3-K9 acetyla- were rapidly identified that clarified the mechanism of tion and H3-K4 methylation are associated with active active repression of transcription. For example, the transcription. In contrast, loss of histone H3-K9 transcription factor Max is the heterodimeric binding acetylation and gain of H3-K9 and H3-K27 methylation partner of both the transcriptional activator Myc and is indicative of heterochromatin (Maison et al., 2002). In the transcriptional repressor Mad. Both Myc–Max and many cases, modifications of a single residue are Mad–Max heterodimers bind the same E box-contain- mutually exclusive. Furthermore, the presence of one ing DNA sequence, but Mad–Max complexes associate modification may set the stage for additional modifica- with the mSin3 scaffold protein that recruits HDAC1 tions at nearby amino acids, thus expanding the coding and HDAC2. Transcriptional repression of Mad–Max information. Adding another layer of complexity, target genes requires HDAC activity (Hassig et al., 1997; Oncogene HDACs and cancer MA Glozak and E Seto 5422 transcription Ac Ac Ac Ac HAT K K K K KKKK TF Pol transcription II HDAC Ac Ac Ac Ac HAT KKKK K K K K TF Pol HDAC II transcription HDACi Figure 2 The balance between histone acetylation and deacetylation determines the level at which a gene is transcribed. Histone acetylation relaxes the chromatin, allowing transcription factor (TF) binding and RNA polymerase II (pol II) recruitment.