转移性去势抵抗性前列腺癌 (mCRPC) 是一种致命疾病，可抵抗针对雄激素信号传导的治疗，而雄激素信号传导是前列腺癌的主要驱动因素。 mCRPC 通过放大 AR 信号传导或演变成不依赖于 AR 的治疗耐药亚型来抵抗雄激素受体 (AR) 抑制剂。阐明这些亚型的表观遗传基础可以为治疗耐药的驱动因素提供重要的见解。在这项研究中，我们通过对 70 个 mCRPC 组织活检进行 ATAC 测序，并结合转录组和全基因组测序，生成了与谱系特异性转录因子 (TF) 结合相关的染色质可及性图。 mCRPC 具有与 AR 功能相关的独特的全局染色质可及性特征。对可及染色质中 TF 占用的分析揭示了 203 个与 mCRPC 亚型相关的 TF。值得注意的是，ZNF263 被确定为假定的前列腺癌 TF，对双阴性（AR-神经内分泌-）亚型的基因活性具有显着影响，可能激活 MYC 靶点。总体而言，对 mCRPC 染色质可及性的分析为了解 mCRPC 进展过程中发生的表观遗传变化提供了宝贵的见解。

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease that resists therapy targeting androgen signaling, the primary driver of prostate cancer. mCRPC resists androgen receptor (AR) inhibitors by amplifying AR signaling or by evolving into therapy-resistant subtypes that do not depend on AR. Elucidation of the epigenetic underpinnings of these subtypes could provide important insights into the drivers of therapy resistance. In this study, we produced chromatin accessibility maps linked to the binding of lineage-specific transcription factors (TF) by performing ATAC sequencing on 70 mCRPC tissue biopsies integrated with transcriptome and whole genome sequencing. mCRPC had a distinct global chromatin accessibility profile linked to AR function. Analysis of TF occupancy across accessible chromatin revealed 203 TFs associated with mCRPC subtypes. Notably, ZNF263 was identified as a putative prostate cancer TF with a significant impact on gene activity in the double-negative (AR- neuroendocrine-) subtype, potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC.