Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.

中文翻译：

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ONECUT2是致命性前列腺癌的可靶向靶向主调节剂，可抑制雄激素轴。

通过雄激素抑制治疗前列腺癌（PC）促进了雄激素受体（AR）独立的侵略性变体的出现。在这里，我们确定转录因子ONECUT2（OC2）是转移性去势抵抗性前列腺癌（mCRPC）中AR网络的主要调控因子。OC2在mCRPC模型中充当生存因子，通过直接调控AR目标基因和AR许可因子FOXA1抑制AR转录程序，并激活与神经分化和发展为致死性疾病相关的基因。OC2在人类前列腺腺癌和神经内分泌肿瘤的大部分子集中表现出活性。新发现的小分子对OC2的抑制作用可抑制小鼠的转移。这些发现表明，在许多仍保留AR但绕开其活性的情况下，OC2取代了依赖AR的生长和生存机制。在侵袭性PC转移阶段，OC2也是潜在的药物靶标。