Mechanism of epigenetic activation during disease progression

Division Of Basic Sciences - Nci

Investigators

Abstract

In previous work, we showed that activation of an enhancer of AR occurs in response in response to androgen-targeted therapies and contributes to castration-resistance by increasing AR expression. Since that discovery, multiple laboratories have confirmed that the AR enhancer is frequently amplified in castration-resistant prostate cancers and associated with resistance to anti-androgen therapy. However, the mechanism of how the enhancer is activated during the transition from primary prostate cancer, where it is almost never active, to castration-resistant disease, where it is active in 80-90% of cancers, is unknown. To elucidate the mechanism of enhancer activation we are taking a functional genomics approach to identify cis-regulatory elements and trans-acting factors required for AR enhancer activity in a cell line model. In FY23, we identified trans-acting factors that are required for enhancer activity in multiple models. Suppression of these factors results in decreased enhancer mediated AR transcription. We also initiated proteomic studies as an orthogonal unbiased method to identify proteins required for AR enhancer activity. Recently it was shown that histone arginine methyltransferases, PRMT1 and PRMT5, are novel regulators of AR signaling, however, the mechanisms remain poorly understood. In FY23, we began investigations to explore the epigenetic consequences of PRMT1/5 inhibition including effects on chromatin modifications and three-dimensional structure. We hypothesize that targeting PRMT1/5 mediated regulation of AR may provide a therapeutic opportunity in advanced prostate cancers.