Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]. Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence [Tissue ChIP-Seq]

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target. Overall design: AR, FOXA1 and H3K27ac ChIP-seq data on primary prostate carcinomas before and after neoadjuvant enzalutamide therapy. The raw sequencing data cannot be stored with GEO due to patient privacy and was uploaded to the European Genome/Phenome Archive (EGAS00001006017). For tissue ChIP-seq and RNA-seq, the raw sequencing data cannot be stored with GEO due to patient privacy and had to be uploaded to the European Genome/Phenome Archive (ChIP-seq: EGAS00001006017, RNA-seq: EGAS00001006016).

在前列腺癌的治疗中，靶向雄激素受体（androgen receptor, AR）的药物在疾病各阶段均展现出卓越的临床疗效，但治疗耐药性不可避免地出现，目前学界对肿瘤细胞如何通过适应性机制规避AR抑制的具体机制仍知之甚少。本研究针对一项新辅助临床试验中纳入的高危前列腺癌患者，采集其在接受3个月靶向AR的恩扎卢胺单药治疗前后分离的组织样本，开展整合多组学分析。转录组学分析显示，AR抑制可诱导肿瘤向神经内分泌样疾病表型转变。此外，表观基因组分析揭示，恩扎卢胺诱导先驱因子FOXA1发生大规模重编程：其结合位点从非活性染色质结合区域，转向调控促存活信号通路的活性顺式调控元件。值得注意的是，治疗诱导产生的FOXA1结合位点显著富集于昼夜节律核心组分ARNTL的调控区域。治疗后ARNTL的表达水平与患者不良预后显著相关，且抑制ARNTL可在体外降低肿瘤细胞的增殖能力。本研究揭示了AR靶向治疗后FOXA1的顺式调控组可塑性，并发现肿瘤获得了对昼夜节律调控因子ARNTL的依赖性，ARNTL可作为新型候选治疗靶点。整体实验设计：包含新辅助恩扎卢胺治疗前后的原发性前列腺癌组织的AR、FOXA1及H3K27ac染色质免疫共沉淀测序（ChIP-seq）数据。由于涉及患者隐私，相关原始测序数据无法存储于基因表达综合数据库（Gene Expression Omnibus, GEO），已上传至欧洲基因组与表型组档案馆（EGAS00001006017）。针对组织样本的ChIP-seq与RNA测序（RNA-seq）原始数据，同样因患者隐私无法存储于GEO，分别上传至欧洲基因组与表型组档案馆（ChIP-seq: EGAS00001006017，RNA-seq: EGAS00001006016）。