Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in prostate cancer

Next generation antiandrogens such as enzalutamide (Enz) are effective initially for the treatment of castration-resistant prostate cancer (CRPC). However, the disease often relapses and the underlying mechanisms remain elusive. By performing H3-lysine-27 acetylation (H3K27ac) ChIP-seq in Enz-resistant CRPC cells, we identified a group of super enhancers (SEs) that are abnormally activated in Enz-resistant CRPC cells and associated with enhanced transcription of a subset of tumor promoting genes such asCHPT1, which catalyzes phosphatidylcholine (PtdCho) synthesis and regulates choline metabolism. Increased CHPT1 conferred CRPC resistance to Enz in vitro and in mice. While androgen receptor (AR) primarily binds to a putativeCHPT1enhancer and mediates androgen-dependent expression ofCHPT1gene in Enz-sensitive prostate cancer cells, AR binds to a different enhancer within theCHPT1SE locus and facilities androgen-independent expression ofCHPT1in Enz-resistant cells. We further identified a long-non coding RNA transcribed atCHPT1enhancer (also known as enhancer RNA) that binds to the H3K27ac reader BRD4 and participates in regulatingCHPT1SE activity andCHPT1gene expression. Our findings demonstrate that aberrantly activated SE upregulates CHPT1 expression and confers Enz resistance in CRPC, suggesting that SE-mediated expression of downstream effectors such as CHPT1 can be viable targets to overcome Enz resistance in PCa.