PDF(Pubmed)
Abstract：
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.
摘要：
雄激素受体-（AR-）冷漠是前列腺癌（PC）对激素治疗的抵抗机制。在这里，我们证明ONECUT2（OC2）通过与腺癌相关的多个驱动因素激活抵抗，茎样和神经内分泌（NE）变体。直接的OC2基因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，OC2，尽管其先前描述的NEPC驱动程序功能，可以通过GR的表观遗传激活间接激活AR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的药理学抑制抑制由AR信号传导抑制剂恩杂鲁胺诱导的谱系可塑性重编程。这些结果证明,OC2活化促进与PC中的治疗引起的谱系变异相关的一系列耐药机制,并且支持作为抑制治疗抗性疾病的手段的治疗靶向OC2的增强努力。
