The transcription factor ONECUT2 is a core regulator of metastatic castration-resistant prostate cancer.

  • Major finding: The transcription factor ONECUT2 is a core regulator of metastatic castration-resistant prostate cancer.

  • Concept: ONECUT2 represses the AR transcriptional program and activates neuroendocrine differentiation genes.

  • Impact: A small-molecule inhibitor of ONECUT2 suppresses prostate cancer growth and metastasis in mice.

Androgen-deprivation therapy in prostate cancer often results in the emergence of aggressive tumors that are androgen-independent or express heterogeneous levels of androgen receptor (AR), suggesting that other transription factors may contribute to the progression to metastatic castration-resistant prostate cancer (mCRPC). Using unbiased bioinformatic analysis of transcriptome datasets, Rotinen, You, and colleagues identified the transcription factor ONECUT2 as a master regulator in mCRPC. ONECUT2 expression and activity was inversely correlated with AR signatures and increased from benign prostate tissue to high-grade tumors. Gene expression profiling and chromatin immunoprecipitation sequencing analysis showed that ONECUT2 suppressed the AR transcriptional program via direct repression of both AR target genes and FOXA1, which encodes an AR pioneer factor that is downregulated in the transition to neuroendocrine prostate cancer (NEPC). Consistent with a role for ONECUT2 in promoting progression to neuroendocrine mCRPC, ONECUT2 activated the expression of genes associated with neuroendocrine differentiation, whereas ONECUT2 expression was negatively regulated by REST, a repressor of neuronal differentiation that is lost in NEPC. Furthermore, ONECUT2 expression was elevated in pretreatment biopsies of metastatic human prostate cancer, with the highest expression in neuroendocrine tumors, and was associated with risk of biochemical recurrence. Depletion of ONECUT2 or treatment with a small-molecule inhibitor that disrupts binding of the ONECUT2 HOX domain to DNA suppressed the growth and metastasis of mCRPC cells both in vitro and in vivo. These results define ONECUT2 as a central transcriptional regulator of mCRPC tumors characterized by decreased AR activity and acquisition of neuroendocrine features and suggest that therapeutic inhibition of ONECUT2 may limit metastasis of aggressive prostate cancer.

Rotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang W-C, et al. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med 2018;24:1887–98.

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