NCOR2 controls androgen deprivation therapy failure in advanced prostate cancer through re-wiring of the onco-epigenome [RNA-seq]

NCOR2 is frequently and significantly mutated in late stage androgen deprivation therapy resistant prostate cancer (ADT-RPCa). NCOR2 has been characterized as a transcriptional corepressor and has mechanistic links to DNA methylation, but its global functions and overall contributions to PCa progression remain enigmatic. We mapped the dihydrotestosterone (DHT) dependent and independent effects of NCOR2 on the transcriptome, cistrome and DNA methylome in androgen sensitive (AS) and ADT-RPCa cells using the isogenic LNCaP and LNCaP-C4-2 (C4-2) cell models and the CWR22 xenograft model of ADT-RPCa. Overall design: total RNA was isolated from androgen sensitive (LNCaP) and androgen therapy resistant (LNCaP-C42) prostate cancer cell lines after 6hr treatment (EtOH or 10nM DHT) .

NCOR2在晚期雄激素剥夺治疗抵抗性前列腺癌（androgen deprivation therapy resistant prostate cancer, ADT-RPCa）中高频且显著发生突变。NCOR2已被鉴定为转录共抑制因子，且与DNA甲基化存在机制层面的关联，但其在前列腺癌（prostate cancer, PCa）进展中的全局功能与整体贡献仍有待阐明。本研究采用同基因系LNCaP与LNCaP-C4-2（C4-2）细胞模型，以及ADT-RPCa的CWR22异种移植模型，绘制了NCOR2在雄激素敏感（androgen sensitive, AS）细胞与ADT-RPCa细胞中，依赖与非依赖双氢睾酮（dihydrotestosterone, DHT）的转录组、顺式调控组（cistrome）与DNA甲基化组调控效应谱。实验总体设计：将雄激素敏感型（LNCaP）与雄激素治疗抵抗型（LNCaP-C42）前列腺癌细胞系分别经6小时处理（乙醇对照或10nM双氢睾酮）后，提取总RNA。