AHR plays important roles in mediating diverse responses to Enzalutamide in prostate cancer

Enzalumatide (ENZ) is a widely used second generation nonsteroidal Androgen Receptor inhibitor that is integral in managing castration-resistant prostate cancer (CRPC). However, resistance inevitably develops in months and limits the clinical benefits of ENZ. AHR is commonly upregulated in ENZ-resistant (ENZR) cell lines and is essential for ENZR CRPC growth in vitro and in vivo. Interestingly, the canonical AHR xenobiotic pathway does not seem to play a role. To characterize, for the first time, transcriptional targets of AHR in prostate cancer, we performed ChIP-seq of AHR and H3K9ac, a marker of active chromatin, in CWR-R1ENZR cells. An AHR knockdown cell line is also included to identify the difference of AHR trancriptional action. ChIP-seq results revealed that AHR binds to multiple genes targeted by AR and glucocorticoid receptor (GR), a well-established mechanism bypassing the AR blockade of ENZ. Furthermore, AHR also binds to many marker genes of neuroendocrine (NE) differentiation, a feature indicating AR-independence and clinical aggressiveness in prostate cancer. Together, these results depict AHR as an important regulator of reponses to ENZ in CRPC.