ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (ATAC-seq)

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) directly activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. 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. Overall design: Compare the chromatin accessibility changes after the overexpression OC2 gene in LNCaP cells. Compare the chromatin accessibility changes after 7 days of vehicle control, enzalutamide treatment (10uM), and combination treatment (Enzalutamide (10uM) + OC2 inhibitor (10uM)).

雄激素受体（androgen receptor, AR）不敏感性是前列腺癌（prostate cancer, PC）内分泌治疗耐药的机制之一。本研究证实，HOX/CUT家族转录因子ONECUT2（OC2）可通过多种与腺癌、干细胞样及神经内分泌（neuroendocrine, NE）亚型相关的驱动因子直接介导耐药发生。OC2通过结合启动子、增强染色质开放性以及形成新型超级增强子（super-enhancers）调控基因表达。对OC2进行药物抑制，可阻断由雄激素信号通路抑制剂恩扎卢胺（enzalutamide）诱导的细胞谱系可塑性重编程。上述研究结果表明，OC2激活可介导一系列与前列腺癌治疗后出现的谱系变异相关的耐药机制。
实验设计：1. 检测LNCaP细胞过表达OC2基因后的染色质开放性变化；2. 对比经7天溶剂对照、恩扎卢胺（10μM）单药处理，以及恩扎卢胺（10μM）联合OC2抑制剂（10μM）处理后的细胞染色质开放性差异。