Abstract 5425: Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate cancer

Abstract

Abstract Background Prostate cancer (PCa) is now the most commonly diagnosed malignancy in men worldwide. SOC combines radiotherapy with ADT, however recurrence rate remains unacceptably high and many men present with late stage aggressive and metastatic disease, with poor prognosis and limited treatment options. Despite tumor suppressor p53 being mutated in approximately 50% of human tumors, it has been reported that p53 alteration occurs in only 12% of primary prostate tumors. Emerging data links epigenetic-mediated gene silencing as a major differentiator between aggressive and indolent disease that is associated with up-regulation of key cell cycle regulator FOXM1, which is known to be suppressed by p53. HDAC inhibitors (HDACi) are an emerging class of epigenetic modifying anti-cancer agents, which we hypothesises will enhance p53 activity, cell death and alter patterns of gene expression to targeting p53 dependent and independent vulnerabilities in PCa. Methods We used basally p53 deficient/proficient PCa models (PC3/LNCaP) and novel C4-2B and LNCap p53 CRISPR-Cas9 knockout models to investigate the combination effects of Nutlin 3A or radiation (IR) with class 1 HDACi Entinostat by Annexin V/PI Flow Cytometry and Western Blot. Transcriptional effects were evaluated by RT-PCR and RNA-seq analysis. TCGA mutational and RNA-seq data were used to link p53 mutation with altered gene expression and outcome. Results We have demonstrated that there is a synergistic induction of cell death when we combine N3A/IR with Entinostat that is p53-dependent. In addition, we see that p53 acts as a barrier to genes associated with poor prognosis including FOXM1 which is phenocopied by single-agent Entinostat independent of WT-p53. This suppression may potentially be downstream of p21 via the DREAM complex. Importantly p53 mutation in TCGA primary PCa patients is associated with poor outcome and elevated FOXM1 expression. Conclusion and Future Work Results to date suggest that Entinostat enhances p53 dependent cell death but also has p53 dependent and independent mechanisms to suppress genes associated with poor prognosis PCa. The mechanism looks to be dependent of p21 and may involve DREAM complex. Citation Format: Gemma M. Gregg, Fiammetta Falcone, Andrea Lees, Gerard Quinn, Peter Gallagher, Richard Kennedy, Ian I. Mills, Simon S. McDade. Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5425.