Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Division of Molecular Oncogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Mol Oncol. 2021 Jul;15(7):1942-1955. doi: 10.1002/1878-0261.12923. Epub 2021 Mar 11.
The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP-seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC-Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.
转移性前列腺癌中转录程序的表观基因组调控机制还不甚清楚。我们通过对从单个前列腺癌患者中衍生的四个克隆转移肿瘤进行转录组分析和 ChIP-seq 分析，研究了前列腺癌驱动因子的表观基因组图谱。我们的表观基因组分析主要集中在雄激素受体（AR）上，它是前列腺癌中的关键致癌驱动因子，AR 先驱因子 FOXA1、染色质绝缘子 CCCTC 结合因子，以及组蛋白 H3K27ac 和 H3K27me3 的修饰。绝大多数 AR 结合位点在健康前列腺、原发性前列腺癌和转移性肿瘤样本中是共享的，这表明在前列腺细胞谱系中存在核心的 AR 驱动的转录调控。与核心 AR 结合事件相关的基因在前列腺癌细胞增殖的必需基因中显著富集。值得注意的是，转移性特异性的活跃 AR 结合位点没有表现出不同的转录输出，这表明在转移性样本中存在一个稳健的转录程序。综上所述，尽管 AR 顺式作用元件在表观基因组上存在差异，但我们的数据揭示了克隆性转移性前列腺癌中的一个核心转录程序。
