Prostate cancer (PCa) is the second leading cause of cancer-related mortality in North American men. In recent years, there has been mounting evidence establishing the centrality of epigenetic mechanisms in PCa initiation and progression. Accordingly, various epigenetic genes have been described to collaborate with the androgen receptor (AR) in enabling its oncogenic transcriptional program and aberrantly restoring its activity in metastatic castration resistant PCa (mCRPC). Concordantly, our lab has recently described two epigenetic genes, BRD4 & MLL2, as key co-activators of the AR signaling complex. Furthermore, we have demonstrated the therapeutic benefits of inhibiting the activity of these genes in advanced PCa. Thus, in a setting where invariably all metastatic PCa patients progress to evolve resistance to anti-AR therapy, epigenetic genes emerge as potent co-targets with the promise to improve patient outcomes. To To identify novel AR-collaborating genes, as part of a multi-institutional consortium, our lab had performed comprehensive molecular profiling of 150 mCRPC patient tumors. This study revealed multiple genetic aberrations in chromatin modifier genes. Interestingly, this list comprised of recurrent mutations in the ASXL family of genes in about ~5% of the cases. ASXL family members are epigenetic scaffolding proteins that assemble chromatin modifiers and transcription factors to specific genomic loci with histone modifications. Although intricately involved in the genesis of acute myeloid leukemia, hitherto, no study has comprehensively described the role of ASXL genes in PCa biology. Two members of this family, ASXL1 and ASXL2, are robustly expressed in PCa. Co-immunoprecipitation assays revealed that these proteins also reside in the AR-signaling complex. Notably, siRNA-mediated inhibition of these genes dramatically attenuated proliferation of AR-dependent PCa cells, but had minimal effect on non-neoplastic prostate cells. These preliminary results strongly implicate ASXL genes in the oncogenic re-programming of AR-activity and warrant further investigation towards exploring of their therapeutic value in currently incurable mCRPC.

Citation Format: Abhijit Parolia, Xuhong Cao, Arul Chinnaiyan. Exploring the role of ASXL family of genes in enabling oncogenic AR-signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3347. doi:10.1158/1538-7445.AM2017-3347