Figure 1.

In treatment-naïve prostate adenocarcinoma, the androgen receptor (AR) axis, activated primarily by androgens of testicular origin, drives cancer growth and expression of a transcriptional program of AR-target genes, such as KLK3 (PSA). AR signaling also suppresses neuroendocrine signaling, by keeping REST levels high, which keeps ONECUT2 levels low. Androgen deprivation therapy (ADT), that targets testicular production of testosterone, achieves high initial response rates, but resistance eventually emerges, as CRPC. The decreased activation of AR, due to low ligand levels, leads to lower REST levels, which consequently allows the de-repression of ONECUT2 expression. ONECUT2 suppresses the AR transcriptional program, via at least three mechanisms: (I) ONECUT2 suppresses expression of AR itself; (II) ONECUT2 suppresses expression of FOXA1, a pioneer factor that facilitates AR function, and; (III) a direct antagonistic effect of ONECUT2 on a subset of the AR-regulated transcriptome. Also, high levels of ONECUT2 drive the NEPC transcriptional program, which includes target genes such as PEG10, and increase SMAD3 expression, which regulates hypoxia signaling through modulating HIF1α binding to the chromatin, leading NEPC to be more hypoxic than adeno-CRPC, PSA, prostate-specific antigen; CRPC, castration-resistant prostate cancer; NEPC, neuroendocrine prostate cancer.