Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

中文翻译：

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ONECUT2 在腺癌以及前列腺癌的神经内分泌变异中充当谱系可塑性驱动因素


雄激素受体（AR）冷漠是前列腺癌（PC）激素治疗的一种抵抗机制。在这里，我们证明 ONECUT2 (OC2) 通过与腺癌、干细胞样和神经内分泌 (NE) 变异相关的多个驱动因素激活耐药性。 OC2 基因的直接靶标包括糖皮质激素受体（GR；NR3C1）和 NE 剪接因子 SRRM4，它们是谱系可塑性的关键驱动因素。因此，尽管 OC2 具有先前描述的 NEPC 驱动功能，但它可以通过 GR 的表观遗传激活间接激活 AR 顺反子的一部分。 OC2 调节基因表达的机制包括启动子结合、增强全基因组染色质可及性和超级增强子重编程。 OC2 的药理抑制可抑制 AR 信号抑制剂恩杂鲁胺诱导的谱系可塑性重编程。这些结果表明，OC2 激活促进了一系列与 PC 中治疗引起的谱系变异相关的耐药机制，并支持加强以治疗性靶向 OC2 作为抑制治疗耐药疾病的手段的努力。