Restoration of DNA‐binding and growth‐suppressive activity of mutant forms of p53 via a PCAF‐mediated acetylation pathway

Abstract

Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy. In support of this possibility p53 mutants possess a certain degree of conformational flexibility that allows for re-induction of function by a number of structurally different artificial compounds or by short peptides. This raises the question of whether physiological pathways for p53 mutant reactivation also exist and can be exploited therapeutically. The activity of wild-type p53 is modulated by various acetyl-transferases and deacetylases, but whether acetylation influences signaling by p53 mutant is still unknown. Here, we show that the PCAF acetyl-transferase is down-regulated in tumors harboring p53 mutants, where its re-expression leads to p53 acetylation and to cell death. Furthermore, acetylation restores the DNA-binding ability of p53 mutants in vitro and expression of PCAF, or treatment with deacetylase inhibitors, promotes their binding to p53-regulated promoters and transcriptional activity in vivo. These data suggest that PCAF-mediated acetylation rescues activity of at least a set of p53 mutations. Therefore, we propose that dis-regulation of PCAF activity is a pre-requisite for p53 mutant loss of function and for the oncogenic potential acquired by neoplastic cells expressing these proteins. Our findings offer a new rationale for therapeutic targeting of PCAF activity in tumors harboring oncogenic versions of p53.

Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3σ

“…4). This result, while unexpected, is not unparalleled, as a number of studies have shown that mutant p53 protein is capable of binding to its target gene sequences and regulating their expression (Pan and Haines, 2000;O'Farrell et al, 2004;Weisz et al, 2007;Chandrachud and Gal, 2009;Perez et al, 2010;Rasti et al, 2012). Since the mutant p53 did not associate with the 14-3-3s promoter in the absence of plakoglobin (SCC9 cells), this suggests a role for plakoglobin in associating p53 with its target gene promoter(s).…”

SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker

“…The expression of p53R175H, p53G281D or p53G245A in the p53 null H1299 cell lines increased the levels of endogenous CIC protein compared to naive H1299 cells (Figure 2AB), while wild-type p53 did not (Figure 2A, lane 2). In isogenic murine mammary breast cancer cell lines either lacking p53, harboring a wild-type gene or carrying the p53G242A codon (equivalent to the human G245A mutation) [24-26], high CIC levels were seen in cells expressing mutant but not wild-type p53 (Figure 2C). Additionally, down-regulation of p53R280K or p53R273H in MDA-231 or MDA-468 cells, respectively, with the previously described specific p53shRNA [9,24] reduced the levels of endogenous CIC (Figure 2DE).…”

Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53

“…Previously, acetylation of the mutant p53 has been found to restore the DNA binding ability and the growth suppression function. 44 Since p53 methylation at K372 promotes its subsequent acetylation, 40,45 it is possible that KDM3A knockdown might reactivate mutant p53 by increasing p53 acetylation. Growing evidence suggests that breast CSCs are chemoresistant and highly invasive which might be associated with disease relapse.…”