Abstract
Functional loss of the two major tumor repressors, TP53 and RB1, is frequently involved in the emergence and progression of castration-resistant prostate cancer (CRPC). Inactivating mutations in TP53 and RB1 promote lineage variants that suppress the androgen receptor axis and enhance therapy resistance. The present study provides the first evidence that RB1 loss, and not TP53 loss, is sufficient to activate the master regulator transcription factor ONECUT2 (OC2) in mCRPC. OC2 upregulation is common in CRPC and drives metastasis and lineage plasticity, particularly neuroendocrine differentiation, in model systems. Pharmacologic inhibition of OC2 was reported to suppress established human CRPC metastases in mice. Here we show that RB1 silencing in human and mouse prostate cancer models is sufficient to upregulate OC2, at least in part through epigenetic regulation. OC2 expression downregulated TP53 transcription and inactivated RB1 via phosphorylation. OC2 expression and activation in human CRPC correlated with bi- or single-allelic loss of RB1 and inversely with RB1 expression and activity. A small molecule OC2 inhibitor blocked enzalutamide-induced lineage plasticity in vitro. These findings indicate that activation of OC2 in CRPC occurs in response to RB1 inactivation, and that biomarkers of RB1 activity may be useful for stratifying patients refractory to hormone therapy where OC2 is targeted pharmacologically.