Abstract 865: Isolation of WDR77-mediated interaction between androgen receptor and p53 uncovers novel treatment strategy for prostate cancer

Abstract

Abstract The ∼30,000 prostate cancer (CaP) deaths in the United States annually are due to failure of androgen deprivation therapy (ADT). ADT prevents ligand-activation of androgen receptor (AR), which is the main target for treatment of non-organ-confined CaP. ADT fails while CaP remains dependent on AR. Recent NextGen sequencing approaches on ADT-recurrent CaP specimens have confirmed AR amplification, and emergence of gain-of-function AR mutations and forms of AR that do not require ligand-activation. The same sequencing studies also identified a striking enrichment in gain-of-function p53 mutations during ADT. AR and p53 have been recognized as the 2 major genomic drivers of lethal CaP progression, do not interact directly and are not targeted efficiently for therapy in ADT-recurrent CaP. Recently, using a customized gene expression oligoarray, we defined the contribution of 18 clinically relevant coregulators to androgen regulation of 452 AR target genes. Coregulator contribution to AR action was highly gene-specific and context-dependent. Selectivity in dependence of AR target genes on individual coregulators was reflected in the composition of associated AR binding sites, as well as in CaP cell biology and clinical CaP progression that was controlled by these AR target genes. The existence of diverse AR-coregulator-transcription factor (TF) transcriptional codes was evidenced by WDR77-dependent interaction between AR and p53. In this novel AR-, p53- and WDR77-dependent transcriptional mechanism, the coregulator WDR77 physically and functionally bridged the action of AR and p53. WDR77 controlled selectively androgen regulation of 96 AR target genes that are associated with aggressive CaP and that mediate cell death, DNA replication, recombination and repair. Using Cistrome project tools, binding motifs for p53 were found close to AR binding sites in WDR77-dependent AR target genes, and ChIP validated androgen-dependent recruitment of p53 and WDR77 to those genomic regions. Genome-wide gene expression profiling confirmed significant overlap (n = 262) in p53- and WDR77-dependent androgen-responsive genes in CaP cells. Co-immunoprecipitation and mammalian-2-hybrid assays demonstrated p53 and WDR77 interaction, and delineated the p53-WDR77 interacting domains. In conclusion, WDR77-dependent interaction between AR and p53 provides the rationale for a novel CaP treatment strategy, namely disruption of functional interaction(s) between AR and TFs, such as p53, that control the CaP biology responsible for lethal disease progression. Citation Format: Sangeeta Kumari, Simon Schlanger, Dan Wang, Song Liu, Hannelore Heemers. Isolation of WDR77-mediated interaction between androgen receptor and p53 uncovers novel treatment strategy for prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 865.