Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.

中文翻译：

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前列腺癌胃肠转录回路的异常激活介导去势抵抗。

前列腺癌表现出对雄激素信号传导的谱系特异性依赖性。去势抵抗涉及雄激素信号的重新激活或替代谱系程序的激活以绕过雄激素需求。我们描述了约 5% 的原发性前列腺癌和约 30% 的去势抵抗性前列腺癌中表达的异常胃肠道谱系转录组，其特征是对雄激素剥夺治疗的反应缩短。该程序由 HNF4G 和 HNF1A 组成的转录回路控制。Cistrome 和染色质分析表明，HNF4G 是在胃肠道谱系基因上产生和维持增强子景观的先锋因子，不依赖于雄激素受体信号传导。在 HNF4G/HNF1A 双阴性前列腺癌中，HNF4G 在生理水平的外源表达重现了胃肠道转录组、染色质景观，并导致相对的去势抵抗。