We have dissected the role of
Estrogen receptor beta (ERβ) in
prostate cancer (PCa) with a novel ERβ
ligand, OSU-ERb-12. Drug screens revealed additive interactions between OSU-ERB-12 and either epigenetic inhibitors or the
androgen receptor antagonist,
Enzalutamide (Enza). Clonogenic and cell biolody studies supported the potent additive effects of OSU-ERB-12 (100nM) and Enza (1μM). The cooperative behavior was in PCa cell lines treated with either OSU-ERB-12 plus Enza or combinations involving 17β-estradiol (E2). OSU-ERb-12 plus Enza uniquely impacted the transcriptiome, accessible
chromatin, and the AR, MYC and H3K27ac cistromes. This included skewed transcriptional responses including suppression of the
androgen and MYC transcriptomes, and repressed MYC
protein. OSU-ERb-12 plus Enza uniquely impacted
chromatin accessibility at approximately 3000
nucleosome-free sites, enriched at enhancers, enriched for basic Helix-Loop-Helix motifs. CUT&RUN experiments revealed combination treatment targeting of MYC, AR, and H3K27ac again shaping enhancer accessibility. Specifically, it repressed MYC interactions at enhancer regions enriched for bHLH motifs, and overlapped with publicly-available bHLH cistromes. Finally, cistrome-transcriptome analyses identified ~200 genes that distinguished advanced PCa
tumors in the SU2C cohort with high
androgen and low neuroendocrine scores.