Advanced prostate cancer initially responds to androgen deprivation therapy (ADT), but the disease inevitably recurs as castration-resistant prostate cancer (CRPC). Although CRPC initially responds to abiraterone and enzalutamide, the disease invariably becomes nonresponsive to these agents. Novel approaches are required to circumvent resistance pathways and to extend survival, but the mechanisms underlying resistance remain poorly defined. Our group previously showed the histone lysine-N-methyltransferase EZH2 to be overexpressed in prostate cancer and quantitatively associated with progression and poor prognosis. In this study, we screened a library of epigenetic inhibitors for their ability to render CRPC cells sensitive to enzalutamide and found that EZH2 inhibitors specifically potentiated enzalutamide-mediated inhibition of proliferation. Moreover, we identified antisense oligonucleotides (ASO) as a novel drug strategy to ablate EZH2 and androgen receptor (AR) expression, which may have advantageous properties in certain settings. RNA-seq, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin using sequencing demonstrated that EZH2 inhibition altered the AR cistrome to significantly upregulate AR signaling, suggesting an enhanced dependence of CRPC cells on this pathway following inhibition of EZH2. Combination treatment with ASO targeting EZH2 and AR transcripts inhibited prostate cancer cell growth in vitro and in vivo better than single agents. In sum, this study identifies EZH2 as a critical epigenetic regulator of ADT resistance and defines ASO-based cotargeting of EZH2 and AR as a promising strategy for the treatment of CRPC.Significance: Simultaneous targeting of lysine methyltransferase EZH2 and the AR with ASO proves a novel and effective therapeutic strategy in patients with CRPC. Cancer Res; 78(20); 5731-40. ©2018 AACR.

Cancer research. 2018 Aug 22 [Epub]

Lanbo Xiao, Jean C Tien, Josh Vo, Mengyao Tan, Abhijit Parolia, Yajia Zhang, Lisha Wang, Yuanyuan Qiao, Sudhanshu Shukla, Xiaoju Wang, Heng Zheng, Fengyun Su, Xiaojun Jing, Esther Luo, Andrew Delekta, Kristin M Juckette, Alice Xu, Xuhong Cao, Ajjai S Alva, Youngsoo Kim, A Robert MacLeod, Arul M Chinnaiyan

Michigan Center for Translational Pathology, Ann Arbor, Michigan., Ionis Pharmaceuticals, Carlsbad, California., Michigan Center for Translational Pathology, Ann Arbor, Michigan. .