Histone Deacetylases Specifically Down-regulate p53-dependent Gene Activation

Abstract

p53, the most commonly mutated gene in cancer cells, directs cell cycle arrest or induces programmed cell death (apoptosis) in response to stress. It has been demonstrated that p53 activity is up-regulated in part by posttranslational acetylation. In agreement with these observations, here we show that mammalian histone deacetylase (HDAC)-1, -2, and -3 are all capable of downregulating p53 function. Down-regulation of p53 activity by HDACs is HDAC dosage-dependent, requires the deacetylase activity of HDACs, and depends on the region of p53 that is acetylated by p300/CREB-binding protein (CBP). These results suggest that interactions of p53 and HDACs likely result in p53 deacetylation, thereby reducing its transcriptional activity. In support of this idea, GST pull-down and immunoprecipitation assays show that p53 interacts with HDAC1 both in vitro and in vivo. Furthermore, a pre-acetylated p53 peptide was significantly deacetylated by immunoprecipitated wild type HDAC1 but not deacetylase mutant. Also, coexpression of HDAC1 greatly reduced the in vivo acetylation level of p53. Finally, we report that the activation potential of p53 on the BAX promoter, a natural p53-responsive system, is reduced in the presence of HDACs. Taken together, our findings indicate that deacetylation of p53 by histone deacetylases is likely to be part of the mechanisms that control the physiological activity of p53.

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells

“…This dependence appears to vary with the agent used and may be due to differences in potency. Furthermore, acetylation of p53 occurs following HDAC inhibitor administration and may increase its activity and reduce targeting of p53 for degradation [22,39,40]. However, others have shown HDAC inhibitors to have apoptotic effects independent from p53 [41].…”

“…Many of these effects were originally thought to be due to hyperacetylation of histones and activation of previously silenced genes. However, it appears that these agents cause hyperacetylation of a variety of proteins, the subject of recent studies [22,23]. It has been suggested that the tumor specificity of these agents is related to their ability to induce apoptosis [24].…”

Modulation of cellular radiation responses by histone deacetylase inhibitors

“…The p53 gene is negatively regulated by HDACs and the protein is a known substrate for HATs and HDACs (Sakaguchi et al, 1998;Luo et al, 2000). Indeed, in response to DNA damage p53 is acetylated at lysine residues in the C-terminal region by the HATs, p300 and PCAF which is thoughtalong with phosphorylation -to stabilize the molecule and it is accumulated in the nucleus where it regulates transcription (Sakaguchi et al, 1998;Juan et al, 2000;Luo et al, 2000). Among numerous other functions, activated p53 induces transcription of a series of proapoptotic Bcl-2 family members (Oda et al, 2000;Nakano and Vousden, 2001).…”

Antibody response to a non‐conserved C‐terminal part of human histone deacetylase 3 in colon cancer patients

“…1,2 Histone deacetylases (HDAC) represent the family of enzymes involved in dynamic regulation of chromatin structure during transcription, but can also deacetylate a number of non-histone substrates. [3][4][5][6][7][8][9] A growing body of evidence implicates HDAC as playing an important role in carcinogenesis, particularly, in colorectal cancer, as suggested by expression profiling of colon cancer cells treated by HDAC inhibitor trichostatin A. [3][4][5] Histone deacetylases may be involved in carcinogenesis in different ways.…”

“…Class I HDAC may downregulate tumor suppressors such as p53 and von Hippel-Lindau (VHL) gene product. [6][7][8] HDAC1 may also affect cancer progression by inhibiting estrogen receptor alpha (ER-a) protein expression and its transcriptional activity. 9 Recent experiments with siRNA for Class I and Class II HDAC demonstrated that the former (particularly HDAC1 and HDAC3) are implicated in regulation of proliferation and survival of cancer cells.…”