Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachussetts, USA.
Gut. 2022 May;71(5):938-949. doi: 10.1136/gutjnl-2020-322835. Epub 2021 May 31.
Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.
We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.
We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as and was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.
Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.
增强子异常开始成为结直肠癌（CRC）的关键表观遗传特征，然而，肿瘤进展过程中染色质状态模式的全面知识、这些模式的异质性以及赋予的治疗机会仍描述得很差。
我们通过对 69 个样本（33 个结直肠腺癌、4 个腺瘤、21 个匹配的正常组织和 11 个结肠癌细胞系）的 222 个染色质谱进行全面的表观基因组特征分析，分别为 6 个组蛋白修饰标记物（Pol II 结合和 CpG 丰富启动子的 H3K4me3、 poised 增强子的 H3K4me1、增强子和转录活跃启动子的 H3K27ac、转录区域的 H3K79me2、多梳抑制区的 H3K27me3 和异染色质的 H3K9me3）。
我们证明 H3K27ac 标记的活跃增强子状态可以区分 CRC 进展的不同阶段。通过表观基因组编辑，我们提供了证据表明，肿瘤特异性增强子的获得对于关键致癌基因，如 和 ，是过度增殖所必需的。一致地，在 CRC 患者来源的异种移植模型中，发现 MEK 加溴结构域抑制的联合具有协同作用。在探测肿瘤间异质性时，我们确定了四个不同的增强子亚型（基于 Epi 基因组的分类，EpiC），其中三个与先前定义的转录组亚型（共识分子亚型，CMSs）密切相关。重要的是，CMS2 可以分为两个具有显著生存差异的 EpiC 亚组。利用这种相关性，我们设计了一种增强子阻断溴结构域抑制剂与特定通路抑制剂（PARPi、EGFRi、TGFβi、mTORi 和 SRCi）的组合治疗策略，用于 EpiC 组。
我们的数据表明，活跃增强子的动态是 CRC 进展的基础，并且可以利用患者特异性增强子模式来进行精确的组合治疗。
