Class II histone deacetylases: versatile regulators

Abstract

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into three classes based on their similarity to known yeast factors: class I HDACs are similar to the yeast transcriptional repressor yRPD3, class II HDACs to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. We discuss their emerging biological functions and the molecular mechanisms by which they are regulated.

Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients

“…HDACs 4, 5 and 7 bind and inhibit MEF2 proteins, which play a significant transcriptional regulatory role in myogenesis. 10,11 In heart, the signal-resistant mutants of class II HDACs render cardiomyocytes resistant to hypertrophic signals, while knockout mice lacking a class II HDAC develop massive cardiac hypertrophy. 13 Therefore, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy.…”

“…8,9 Mammalian HDACs consist of 2 groups, classical HDAC genes and the recently identified NAD-dependent SIRT family. 10,11 Based on structural and functional similarities, the classical HDAC family is divided into 2 different phylogenetic classes: class I and class II. Class I HDACs (HDACs 1-3 and 8) are most closely related to yeast RPD3, while class II HDACs (HDACs 4 -7, 9 and 10) share domains with similarity to yeast HDA1.…”

“…Nuclear export of class II HDACs is induced by phosphorylation and interaction with an adaptor protein, 14-3-3. 10,11 These fine regulations suggest that class II HDACs might be involved in cellular differentiation and developmental processes and that their dysregulation may be involved in carcinogenesis. However, alteration of the expression level and the involvement in the clinical course have not been clarified.…”

Prospects: Histone deacetylase inhibitors

“…There is abundant evidence that HDACs are not redundant in their biological function [De Ruijter et al, 2002;Lehrmann et al, 2002;Glaser et al, 2003;Verdin et al, 2003;Marks et al, 2004]. HDACs targets include histones and nonhistone proteins which regulate gene expression and proteins involved in regulation of cell cycle progression, and cell death [Lehrmann et al, 2002;Johnstone and Licht, 2003;Warrener et al, 2003;Di Gennaro et al, 2004;Marks et al, 2004;Rosato and Grant, 2004;Drummond et al, 2005].…”

CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14‐3‐3s

“…The C-terminus of HDAC7 has been shown to associate with transcriptional co-repressors, such as SMRT, N-CoR, mSin3A, and transcription factor HIF1a [11][12][13]. The amino-terminal region of class IIa HDACs contains limited but significant sequence homology and has been shown to be responsible for HDAC association with Cabin, CtBP, MEF2, CaMK I/IV, HP1a, and 14-3-3s [10]. An important feature of the class IIa HDACs is their ability to shuttle between the nucleus and the cytoplasm.…”