A RARγ-SMARCA5 chromatin-remodeling axis stabilizes AR luminal programs and opposes lineage plasticity in prostate cancer.

In prostate cancer (PCa), epigenomic mechanisms drive resistance to androgen receptor (AR) signaling inhibitors, such as enzalutamide (enza). We tested whether retinoic acid receptor gamma (RARγ) shapes the epigenome to direct AR transcription, promote luminal identity, and limit enza resistance. RARγ restoration in enza-resistant 22Rv1 cells induced a large RARγ complex containing its coactivator TACC1 and the chromatin remodeler ISWI ATPase SMARCA5. RARγ restoration expanded and redistributed the AR cistrome toward active promoters, enhancers, and unique super-enhancers and increased the overlap with H3K27ac. RARγ restoration also increased SMARCA5 promoter-proximal binding that overlapped with G2/M-enriched AR cistrome, linking AR redistribution to cell cycle-associated chromatin engagement, including at luminal genes. In 22Rv1 and LNCaP C4-2 (also enza-resistant), RARγ restoration directed the AR transcriptome toward luminal differentiation. A miR-96 antagomir (targeting RARγ) mirrored the impact of RARγ restoration. RARγ antagonized the actions of the master lineage regulator ONECUT2 at the cistrome and transcriptome level and these antagonized genes were significantly associated with alternative lineages in murine PCa models of lineage plasticity and enza responsiveness and lineage plasticity in human PCa cohorts. These findings identify RARγ as a regulator of a chromatin remodeling mechanism that sustains luminal AR programs and opposes therapeutic resistance.