Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8

Abstract

Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here, we found that histone deacetylase inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type but not mutant HDAC8 leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Due to the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.

Mechanism of N-Acylthiourea-mediated Activation of Human Histone Deacetylase 8 (HDAC8) at Molecular and Cellular Levels

“…Such a discriminatory feature appears to be encoded in the expression of the wild-type versus mutant forms of the tumor suppressor protein p53 in the above cell lines, respectively. Yan et al (17) recently demonstrated that the transcription of both the wildtype and the mutant p53 genes are regulated via HDAC8 in various human cancer cells (17). In addition, when the cancer cells express the mutant forms of HDAC8 (exhibiting lower catalytic activity), the up-regulation of p53 is obviated.…”

“…Considering the fact that HDAC8 enhances the expression of p53 (17), the treatment of cancers by HDAC inhibitors should be used with caution. This is primarily because the inhibition of HDAC8 (by SAHA and other pan-HDAC inhibitors) would suppress the up-regulation of the wild-type p53 gene, obviating the tumor-protective effects of p53 and p21.…”

“…On the other hand, a variety of acetylated non-histone proteins of nucleus, such as ERR-␣, hEST1B (human ever-shorter telomere 1B), and SMC3, are selectively deacetylated by HDAC8, resulting in the regulation of associated physiological processes (13)(14)(15)(16). Recent studies have shown that HDAC8 regulates the expression of tumor suppressor protein p53 in a HoxA-dependent manner (17), an observation that appears to be corroborated by our cellular studies on SH-SY5Y cells (see "Results").…”

TAp73 Protein Stability Is Controlled by Histone Deacetylase 1 via Regulation of Hsp90 Chaperone Function

“…These results suggest that other HDACs are involved in regulating TAp73 transcription, although the underlying mechanism is not clear. Recently, HDAC8, a class I HDAC, was found to regulate p53 transcription via transcription factor HoxA5 (45). In addition, the activity of E2F1, a known p73 regulator, is found to be regulated by HDACI (61).…”

“…For example, HDAC1 deacetylates p53 and affect its transcriptional activity (42,43), whereas HDAC2 modulates the ability of p53 to bind DNA and p53-dependent transcription (44). Additionally, p53 transcription is found to be regulated by HDAC8 via HoxA5, whereas the protein stability of mutant p53 is found to be regulated by HDAC6-Hsp90 chaperone (45,46). Furthermore, ⌬Np63 transcription is found to be regulated by HDAC2 via Dec1 (47).…”