Abstract 5497: LSD1 modulates androgen receptor cistrome in prostate cancer via regulation of FOXA1 chromatin binding

Abstract

Abstract Patients with castration-resistant prostate cancer (PCa) benefit from CYP17A1 inhibitors and more potent AR antagonists, but still relapse with tumors expressing high levels of AR and AR regulated genes, indicating restoration of AR activity. Therefore, there remains a pressing need for further development of novel AR targeted therapies. One major mechanism that contributes to the PCa development is reprogramming of AR cistrome by transcriptional factors and chromatin modifiers. In this process, AR is recruited to a subset of newly established enhancers that can drive the expression of proliferation genes. FOXA1 is one such transcriptional factor that determines cell-lineage and is characterized as a “pioneer” factor to facilitate the access of additional transcription factors (such as AR or ER) to the regions with compact chromatin. A recent study by comparing the AR cistrome in normal prostate and PCa tissues suggests that FOXA1 is responsible for driving AR reprograming. Whole genome analyses in PCa cells have revealed that FOXA1 can recognize enhancer regions with active histone marks (H3K4me1,2) and then further open up the sites to allow subsequent AR binding. However, the molecular mechanism on how FOXA1 is guided to the target region in PCa is still elusive and studying this mechanism exhibits significant translational potential on modulating AR activity in PCa. Lysine Specific Demethylase 1 (LSD1/KDM1A) is an important epigenetic modifier that can function as a repressor by demethylating H3K4me1,2. However, LSD1 also often associates with enhancers and can function as an activator in some contexts. Our previous studies showed that LSD1 binding significantly overlaps with FOXA1 and the overlapping sites that are marked by high levels of H3K4me2 enrich for AR activated genes. LSD1 also interacts with FOXA1 and this interaction enhances binding of both proteins at AR-mediated enhancers. These findings suggest that LSD1 may regulate the availability of enhancers to AR via interaction with FOXA1 and hence may reprogram AR cistrome in PCa cells. In this study, we performed ChIP-seq analyses of FOXA1 and AR in PCa cells treated with LSD1 inhibitors. The results showed that the global FOXA1 binding was drastically diminished by inhibiting LSD1, indicating that its demethylase activity is required for FOXA1 binding. Importantly, inhibiting LSD1 also results in distinct AR binding patterns with the expression of many classic AR-activated genes being impaired and new AR-activated genes emerged. We are currently carrying out xenograft studies to examine the impact on tumor progression and AR cistrome by LSD1 inhibitor. Overall, our results suggest that the LSD1-FOXA1 interaction functions as an important modulator of AR cistrome and targeting LSD1 in conjunction with AR antagonists may be a promising therapeutic approach to treat PCa. Citation Format: Shuai Gao, Sujun Chen, Dong Han, Wanting Han, Steven P. Balk, Housheng Hansen He, Changmeng Cai. LSD1 modulates androgen receptor cistrome in prostate cancer via regulation of FOXA1 chromatin binding [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 5497. doi:10.1158/1538-7445.AM2017-5497