ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer (RNA-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 transcriptome changes after the overexpression OC2 gene in LNCaP and LAPC4 cells.Compare the transcriptome changes after the knockdown of OC2 gene in LNCaP cells. Compare the transcriptome 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）不敏感是前列腺癌（prostate cancer, PC）内分泌治疗耐药的一种机制。本研究证实，HOX/CUT家族转录因子ONECUT2（OC2）可通过多个与腺癌、干细胞样及神经内分泌（neuroendocrine, NE）亚型相关的驱动因子，直接介导前列腺癌的治疗耐药。OC2可通过结合基因启动子、增强染色质开放状态以及形成新型超级增强子（super-enhancers）的方式调控基因表达。对OC2进行药理学抑制，可阻断AR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。上述结果表明，OC2的激活可促进一系列与前列腺癌治疗后新发谱系变异相关的耐药机制。整体实验设计如下：1. 分别在LNCaP与LAPC4细胞系中过表达OC2基因后，比较二者的转录组变化；2. 在LNCaP细胞系中敲低OC2基因后，分析其转录组改变；3. 设置三组处理：溶剂对照组、恩扎卢胺（10μM）单药处理组以及联合处理组（恩扎卢胺10μM + OC2抑制剂10μM），处理7天后比较各组的转录组差异。