The functional significance of nuclear receptor acetylation.

The endocrine signaling governing nuclear receptor (NR) function has been known for several decades to play a crucial role in the onset and progression of several tumor types. Notably among these are the estrogen receptor (ER) in breast cancer and androgen receptor (AR) in prostate cancer. Other nuclear receptors may be involved in cancer progression including the peroxisome-proliferator activating receptor gamma (PPARgamma), which has been implicated in breast, thyroid, and colon cancers. These NR are phylogenetically conserved modular transcriptional regulators, which like histones, undergo post-translational modification by acetylation, phosphorylation and ubiquitination. Importantly, the transcriptional activity of the receptors is governed by the coactivator p300, the activity of which is thought to be rate-limiting in the activity of these receptors. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), modify histones by adding or removing an acetyl group from the epsilon amino group of lysines within an evolutionarily conserved lysine motif. Histone acetylation results in changes in chromatin structure in response to specific signals. These enzymes can also directly catalyze the NRs themselves, thus modifying signals at the receptor level. The post-translational modification of NR which is regulated by hormones, alters the NR function toward a growth promoting receptor. The deacetylation of NR is mediated by TSA-sensitive and NAD-dependent deacetylases. The regulation of NR by NAD-dependent enzymes provides a direct link between intracellular metabolism and hormone signaling