HDACs and Differentiation

Dysregulation of differentiation is a characteristic of cancer. Through histone deacetylation, HDACs regulate cell differentiation via modulation of the transcription of differentiation-associated genes (Brunmeir et al. 2009; Glozak and Seto 2007; Hisahara et al. 2008). However, only a few nonhistone proteins have been shown to be direct deacetylation substrates of HDACs in differentiation.

The myogenic activator, MyoD, is a deacetylation substrate of HDAC1. MyoD plays an important role in muscle cell differentiation. It interacts with and is acetylated by p300/CBP and PCAF. Acetylation of MyoD at the evolutionarily conserved lysine residues enhances its DNA-binding activity and is necessary for the execution of the muscle program (Polesskaya et al. 2000). HDAC1 directly binds and deacetylates MyoD in vitro and, more importantly, represses MyoD-mediated transcription in vivo by preventing MyoD from converting undifferentiated skeletal muscle cells to mature muscle cells in a deacetylase activity-dependent manner (Mal et al. 2001).

The myocyte enhancer factor 2 (MEF2) was originally identified as a muscle differentiation related-transcription factor involved in the regulation of skeletal muscle development and the stress-response of cardiomyocytes (Lilly et al. 1994; Zhang et al. 2002). Interestingly, MEF2-dependent myogenesis may be simultaneously controlled by three HDACs: HDAC3, HDAC4, and SIRT1 (Zhao et al. 2005; Gregoire et al. 2007). SIRT1 and HDAC3, but not HDAC4, are capable of directly deacetylating MEF2. HDAC4 might act indirectly, and integrate sumoy-lation and deacetylation signals via its interaction with Ubc9 and SIRT1. Because acetylation of MEF2 is inducible upon muscle cell differentiation and enhances its activity, HDAC4-mediated sumoylation is thought to inhibit MEF2 (Zhao et al. 2005).

SIRT1 is also involved in differentiation by deacetylation of the tumor suppressor retinoblastoma protein (Rb). Rb represses gene transcription by directly binding to the transactivation domain of E2F, promoting recruitment of chromatin-remodeling enzymes, such as HDACs, to the E2F-target gene promoters, and facilitating adipocyte differentiation by inducing cell-cycle arrest (Giacinti and Giordano 2006; Zhu 2005). Transient phosphorylation of Rb by G1-specific CDKs is the main mechanism by which Rb activity is regulated (Mittnacht 1998). Acetylation of Rb by p300 at the C-terminus is an additional mechanism to regulate Rb activity, which results in hypo-phosphorylated Rb and causes cell cycle arrest (Chan et al. 2001). Lysine residues in regions of Rb other than the C-terminus could be acetylated by PCAF. Acetylation of these sites affected Rb-mediated terminal cell cycle exit and the induction of late myogenic gene expression, but not Rb-dependent growth arrest (Nguyen et al. 2004). This evidence suggests a role of acetylation in the regulation of the differentiation-specific function of Rb. SIRT1 can deacetylate Rb in response to contact inhibition and DNA-damage, indicating that SIRT1 can negatively regulate Rb and act as a switch to restart the cell cycle (Wong and Weber 2007).

Runt domain transcription factors (RUNXs) play essential roles in both neoplasias and normal development, such as hematopoiesis, osteogenesis, neuro-genesis, and thymopoiesis. Various functions of Runx family are regulated by acetylation and deacetylation (Bae and Lee 2006). Acetylation of Runx1 at K24 and K43 by p300 is required for its transforming ability (Yamaguchi et al. 2009). Runx3 is necessary for T-cell development and serves as a gastric tumor suppressor, and competitive acetylation and deacetylation of Runx3 at three lysine residues modulates its stability. Upon TGF-beta stimulation, p300 bound to Runx3 and acetylated it at K148, K186, and K182. HDAC4 and HDAC5 reduced its acetyla-tion. Acetylation enhanced Runx3 stability by preventing its ubiquitination by Smurf ubiquitin ligases (Jin et al. 2004).

Deacetylation of FOXO1 by SIRT2 and deacetylation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) by HDAC3 may both be involved in the regulation of development and differentiation (Fajas et al. 2002; Jing et al. 2007). SIRT2 modulates adipocyte differentiation through the regulation of FOXO1 acetylation. SIRT2 was found to be downregulated during preadipocyte differentiation in 3T3-L1 cells. Moreover, overexpression of SIRT2 inhibited the differentiation of 3T3-L1, whereas a decrease of SIRT2 promoted adipogenesis. A reduction of SIRT2 affected the acetylation, phosphorylation, and localization of FOXO1 and its function in adipocyte differentiation (Jing et al. 2007). PPAR-gamma, a nuclear receptor pivotal for adipogenesis, promotes adipocyte differentiation more efficiently in the absence of Rb. Both Rb and HDAC3 are reported to attenuate the ability of PPAR-gamma to drive gene expression and adipocyte differentiation. Inhibition of HDAC3 or disruption of the PPAR-gamma-HDAC3- Rb interaction is predicted to stimulate adipocyte differentiation (Fajas et al. 2002).

Five Foods That Build Muscle

Five Foods That Build Muscle

How to properly fuel your body before and after your workouts, with the right nutrients and in the right way, for maximum results week after week! Find out why protein and hardwork is not enough...and why your results will suffer unless you add these other 5 foods to your muscle-building plan.

Get My Free Ebook


Post a comment