Acetylation of nuclear receptors in cellular growth and apoptosis Maofu Fu, Chenguang Wang, Xueping Zhang, Richard G. Pestell * Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd NW, Washington, DC 20057, USA Received 20 March 2004; accepted 24 May 2004 Abstract Post-translational modification of chromatin histones governs a key mechanism of transcriptional regulation. Histone acetylation, together with methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, and ADP ribosylation, modulate the activity of many genes by modifying both core histones and non-histone transcription factors. Epigenetic protein modification plays an important role in multiple cellular processes including DNA repair, protein stability, nuclear translocation, protein–protein interactions, and in regulation of cellular proliferation, differentiation and apoptosis. Histone acetyltransferases modify histones, coactivators, nuclear transport proteins, structural proteins, cell cycle components and transcription factors including p53 and nuclear receptors. The estrogen, PPARg and androgen receptor are members of the nuclear receptor (NR) superfamily. The androgen receptor (AR) and estrogen receptor a (ERa) are directly acetylated by histone acetyl- transferases at a motif that is conserved between species and other NR. Point mutations at the lysine residue within the acetylation motif of the AR and ERa have been identified in prostate cancer as well as in breast cancer tissue. Acetylation of the NR governs ligand sensitivity and hormone antagonist responses. The AR is acetylated by p300, P/CAF and TIP60 and acetylation of the AR regulates co-regulator recruitment and growth properties of the receptors in cultured cells and in vivo. AR acetylation mimic mutants convey reduced apoptosis and enhanced growth properties correlating with altered promoter specificity for cell-cycle target genes. Cell-cycle control proteins, including cyclins, in turn alter the access of transcription factors and nuclear receptors to the promoters of target genes. # 2004 Elsevier Inc. All rights reserved. Keywords: Nuclear receptor; Histone acetyltransferases; Histone deacetylases; Coactivators; Corepressors; Post-translational modification; Cellular growth; Apoptosis 1. Introduction Activation of target genes by hormones requires chro- matin remodeling and histone modifications. Whereas DNA sequences within chromatin serve as genetic code for gene expression, post-translational modifications of core histones comprise an epigenetic ‘‘histone code’’ that modulates the local chromatin structure and determines the accessibility of transcriptional co-regulators to the under- lying DNA. A diverse array of covalent modifications of the amino acid residues in the histone tails including acetylation, phosphorylation, methylation and ubiquityla- tion have been reported. Distinct histone modifications, which act sequentially or in combination, dictate dynamic transitions between transcriptionally active or transcrip- tionally silent chromatin states [1–5]. Post-translational modification of histone proteins as well as non-histone proteins including nuclear receptors integrates signaling pathways mediating diverse biological processes. This review will focus on the biological significance of nuclear receptors modification by acetylation. 2. Histone acetyltransferases and deacetylases In eukaryotes, DNA is packaged by histones into nucleo- somes which are composed of 147 base pairs of DNA and core histone proteins H2A, H2B, H3 and H4. Alterations in the localize chromatin structure has an important impact on genetic transcriptional responses. Chromatin remodeling Biochemical Pharmacology 68 (2004) 1199–1208 0006-2952/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2004.05.037 Abbreviations: NR, nuclear receptor; AR, androgen receptor; ERa, estrogen receptor a; PPARg, peroxisome proliferator-activated receptor g; HATs, histone acetyltransferases; HDACs, histone deacetylases; SRC-1, steroid receptor coactivator-1; N-CoR, nuclear receptor corepressor; SMRT, silencing mediator of retinoid and thyroid hormone receptor; DHT, dihydrotestosterone; TSA, trichostatin A * Corresponding author. Tel.: þ1 202 687 2110; fax: þ1 202 687 6402. E-mail address: pestell@georgetown.edu (R.G. Pestell).