ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (RNA-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 transcriptome changes after the overexpression OC2 gene in LNCaP and LAPC4 cells.Compare the transcriptome changes after the knockdown of OC2 gene in LNCaP cells. Compare the transcriptome changes after 7 days of vehicle control, enzalutamide treatment (10uM), and combination treatment (Enzalutamide (10uM) + OC2 inhibitor (10uM)).