Prostate cancer (Pca) remains the second leading cause of cancer-related deaths in men in the United States. Although advanced Pca usually responds to therapies that suppress androgen-axis signaling, resistance inevitably develops, leading to the emergence of castration-resistant prostate cancer (CRPC). Importantly, the clinical efficacy of novel therapies targeting androgen receptor (AR) signaling, such as abiraterone and enzalutamide, has confirmed that most CRPC cases demonstrate intact AR signaling. Since resistance to these therapies inevitably develops, approaches that improve the response duration and address the key pathways of resistance are warranted. Mechanisms underlying androgen deprivation therapy (ADT) resistance remain poorly defined, but may depend on epigenetic reprogramming. Our group previously showed that EZH2 is overexpressed and associates with Pca progression and poor prognosis. We substantiated this finding by screening a library of epigenetic inhibitors for their ability to render ADT-resistant CRPC cells sensitive to enzalutamide. Of these compounds, the EZH2 inhibitors facilitated a substantial increase in enzalutamide-mediated growth inhibition. Given these data, we hypothesized that EZH2-mediated epigenetic reprogramming might be crucial for the development and maintenance of ADT resistance, and targeting EZH2 might sensitize resistant CRPC cells to ADT. To test this hypothesis, we performed loss-of-function of EZH2 experiments on multiple CRPC cell lines, and determined that loss-of-function of EZH2 significantly sensitized Pca cells to ADT. Interestingly, by employing RNA-seq and ChIP-seq approaches to dissect the regulatory role of EZH2, we found that EZH2 inhibition significantly up-regulates AR signaling by changing the AR cistrome. Further experimentation confirmed that the loss-of-function of EZH2-mediated deregulation of AR signaling strengthens the AR-dependency of Pca, thus increasing the sensitivity of Pca to ADT. To co-target EZH2 and AR with greater efficiency, we employed antisense oligonucleotides (ASOs) directed against EZH2 and AR at the mRNA level. We determined that co-targeting EZH2 and AR by ASOs constitutes a novel, viable therapy for CRPC in vitro and in vivo. In conclusion, we have identified EZH2 as a critical epigenetic regulator for ADT resistance and have shown that co-targeting EZH2 and AR by ASOs to be a promising, potential strategy for preventing and treating CRPC.
Citation Format: Lanbo Xiao, Jean Ching-Yi Tien, Josh Vo, Abhijit Parolia, Lisha Wang, Mengyao Tan, Yuanyuan Qiao, Sudhanshu Shukla, Xiaoju Wang, Heng Zheng, Fengyun Su, Xuhong Cao, Arul Chinnaiyan. Epigenetic re-programming sensitizes prostate cancer cells to anti-androgen therapy [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 5834.