Abstract 3576: USP22 modulates AR activity to critically regulate prostate cancer progression.

Abstract

Abstract Recently, the deubiquitylase Ubiquitin-specific protease 22 (USP22) was identified as a member of the 11 gene ‘death-from-cancer’ signature, which can predict poor response to therapy and/or propensity toward metastasis of multiple tumor types, including breast and prostate. However, the mechanism for how USP22 impacts cancer is currently unknown. Our new data implicate a specific role for USP22 in hormone-dependent cancers, especially prostate cancer (PCa) where USP22 expression is elevated in primary and metastatic PCa. USP22 has an established role in regulating oncogenic c-Myc activity as it is recruited by c-Myc for transcriptional activation through deubiquitylation of histones, and is necessary for c-Myc-mediated cell transformation. Similarly, our data in PCa cells demonstrates that USP22 controls c-Myc activity but does not affect expression levels. Additional data has also identified USP22 as a critical effector of androgen receptor (AR) levels and output. This is of great clinical relevance since PCa is intricately dependent on AR signaling for disease initiation and progression to castrate resistant disease (CRPC). First, USP22 overexpression in hormone-dependent and CRPC cell lines increased AR protein expression and activity, but did not perturb transcript. Second, in the absence of ligand, USP22 upregulation resulted in enhanced AR recruitment to target genes, as determined by chromatin immunoprecipitation, which corresponded with significant enhancement of cell proliferation and BrdU incorporation. Third, USP22 depletion resulted in attenuated AR activity and caused a significant reduction in AR protein levels that could be attributed to protein stability. Importantly, in the CRPC setting, USP22 depletion dramatically inhibited in vivo tumor growth while expression correlated with decreased time for tumor regression. In sum, the data suggest that USP22 upregulation is sufficient for aberrant c-Myc activity, altered AR expression and activity, and establishment of a CRPC phenotype. We propose that modulation of UPS22 expression and/or activity may present a novel platform to achieve combinatorial suppression of AR and c-Myc function, and therefore could be potentially developed as a novel approach for treatment of PCa. Citation Format: Randy Schrecengost, Jeffry Dean, Tim Stanek, Ruth Birbe, Jessica Hicks, Tapio Visakorpi, Angelo DeMarzo, Steve McMahon, Karen Knudsen. USP22 modulates AR activity to critically regulate prostate cancer progression. [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 3576. doi:10.1158/1538-7445.AM2013-3576