ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (CUT&RUN-seq)

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Overall design: Compare the TF binding (OC2, AR, GR) and histone markers (H3K27Ac, H3K4me3, H3K27me3) of CUT&RUN-seq data in LNCaP Vector Control vs. OC2 overexpression cells. Compare the FOXA1 binding change in LNCaP cells after 7 days of vehicle control, enzalutamide treatment (10uM), and combination treatment (Enzalutamide (10uM) + OC2 inhibitor (10uM))