Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.
Cancer Res. 2024 Sep 16;84(18):3086-3100. doi: 10.1158/0008-5472.CAN-24-0890.
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 assay for transposase-accessible chromatin 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 subtype (AR- neuroendocrine-), potentially activating MYC targets. Overall, this analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during progression to mCRPC. Significance: Integration of a large cohort of transcriptome, whole-genome, and ATAC sequencing characterizes the chromatin accessibility changes in advanced prostate cancer and identifies therapy-resistant prostate cancer subtype-specific transcription factors that modulate oncogenic programs.
转移性去势抵抗性前列腺癌（mCRPC）是一种致命疾病，它对靶向雄激素信号的治疗产生抗药性，而雄激素信号是前列腺癌的主要驱动因素。mCRPC 通过放大 AR 信号或演变成不依赖 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 例 mCRPC 组织活检进行转座酶可及性染色质测序（ATAC-seq），与转录组和全基因组测序相结合，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谱。mCRPC 具有与 AR 功能相关的独特的全局染色质可及性特征。对可及染色质上 TF 占据的分析揭示了 203 个与 mCRPC 亚型相关的 TF。值得注意的是，ZNF263 被鉴定为一种潜在的前列腺癌 TF，对双阴性亚型（AR-神经内分泌-）中基因活性有重大影响，可能激活 MYC 靶标。总的来说，这项 mCRPC 染色质可及性分析提供了宝贵的见解，了解了在进展为 mCRPC 过程中发生的表观遗传变化。意义：整合大量的转录组、全基因组和 ATAC 测序，对晚期前列腺癌的染色质可及性变化进行了特征描述，并鉴定了治疗耐药的前列腺癌亚型特异性转录因子，这些因子调节致癌程序。
