Abstract LB-114: Genome wide analysis reveals a "liability" in the mutant p53 transcriptome.

Abstract

Abstract One of the mechanisms by which the oncogene mutant p53 (mtp53) suppresses chemotherapy induced apoptosis is by directly regulating gene expression. We speculated that within the mtp53 transcriptome, there may be transcriptional targets that constitute "liabilities" that can be exploited to kill mtp53 bearing cancer cells. CHIP-Seq analysis of mtp53 revealed that the key enzyme required for activation of nucleoside analogs, deoxycytidine kinase (DCK), is a direct target of mtp53. We demonstrate that mtp53 associates with the promoter of the DCK gene and that knockdown of mtp53 in multiple cancer cell lines results in reduced DCK mRNA and protein levels. Furthermore, we show that mtp53 cooperates with the ETS transcription factors to induce DCK expression. Knockdown of mtp53 or ETS proteins reduces the activity of a DCK promoter-luciferase construct, thus reinforcing that DCK is a transcriptional target of an ETS/mtp53 complex. In contrast, knockdown of wildtype p53 has no effect on the expression of DCK, indicating that the ability of mtp53 to regulate DCK expression is a gain-of-function activity. Based on our findings, we reasoned that by upregulating DCK expression, mtp53 may increase the sensitivity of cancer cells to nucleoside analogs. Indeed, shRNA knockdown of DCK reduces the sensitivity of cancer cells to gemcitabine. Importantly, suppression of mtp53 or ETS proteins also renders cancer cells less sensitive to gemcitabine. Thus, these data support the notion that mtp53 can sensitize cells to nucleoside analogs via DCK. Our data reveal the presence of a transcriptional "liability" in the mtp53 transcriptome that may help predict which patients will have a better therapeutic response to nucleoside analogs. Citation Format: Luis A. Martinez, Madhusudhan Kollareddy, Lakshman Varanasi. Genome wide analysis reveals a "liability" in the mutant p53 transcriptome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2013-LB-114