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 HOX/CUT 转录因子 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 的直接靶标包括糖皮质激素受体和 NE 剪接因子 SRRM4 等。 OC2 通过启动子结合、增强染色质可及性以及形成新型超级增强子来调节基因表达。 OC2 还激活葡萄糖醛酸化基因，从而不可逆地禁用雄激素，从而通过激素消耗间接引起表型异质性。 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治疗引起的 PC 谱系变异相关的耐药机制。我们的研究结果支持加强努力以治疗性靶向这种蛋白质作为抑制难治性疾病的手段。

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4, among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. 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. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.