The Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, 227 Chongqing South Road, Shanghai, China.
Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 510000, 195 Dongfeng West Road, Guangzhou, China.
J Mol Cell Biol. 2020 Feb 20;12(2):125-137. doi: 10.1093/jmcb/mjz032.
Histone methylation is a context-dependent modification that regulates gene expression, and the trimethylation of histone H3 lysine 27 (H3K27me3) usually induces gene silencing. Overcoming colorectal cancer (CRC) chemoresistance is currently a huge challenge, but the relationship between H3K27me3 modification and chemoresistance remains largely unclear. Here, we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment. Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B (KDM6A/6B), thus decreasing the level of H3K27me3 in CRC cells. Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4 (a KDM6A/6B inhibitor) treatment significantly enhanced oxaliplatin-induced apoptosis. Conversely, when inhibiting the expression of H3K27me3 by EPZ-6438, an inhibitor of the histone methyltransferase EZH2, the proportion of apoptotic cells remarkably decreased. In addition, the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model. Importantly, we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression, which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site. Thus, the activated NOTCH signaling promoted the expression of stemness-related genes, which resulted in oxaliplatin resistance. Furthermore, oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment. Collectively, our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
组蛋白甲基化是一种依赖于上下文的修饰，可调节基因表达，而组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）通常会诱导基因沉默。克服结直肠癌（CRC）的化疗耐药性目前是一个巨大的挑战，但 H3K27me3 修饰与耐药性之间的关系在很大程度上仍不清楚。在这里，我们发现 H3K27me3 水平与 CRC 患者的无转移生存时间呈正相关，而 H3K27me3 水平低预示着化疗药物治疗效果不佳。奥沙利铂刺激显著诱导了 H3K27 赖氨酸去甲基化酶 6A/6B（KDM6A/6B）的表达，从而降低了 CRC 细胞中 H3K27me3 的水平。通过 KDM6A/6B 耗竭或 GSK-J4（一种 KDM6A/6B 抑制剂）处理升高 H3K27me3 水平显著增强了奥沙利铂诱导的细胞凋亡。相反，当通过 EZH2 的组蛋白甲基转移酶抑制剂 EPZ-6438 抑制 H3K27me3 的表达时，凋亡细胞的比例明显降低。此外，GSK-J4 和奥沙利铂的联合治疗显著抑制了奥沙利铂耐药患者来源异种移植模型中的肿瘤生长。重要的是，我们揭示了奥沙利铂处理显著诱导了 NOTCH2 的表达，这是由于 NOTCH2 转录起始位点 H3K27me3 水平的下调所致。因此，激活的 NOTCH 信号促进了干性相关基因的表达，导致了奥沙利铂耐药。此外，GSK-J4 处理可阻断奥沙利铂诱导的 NOTCH 信号。总之，我们的研究结果表明，提高 H3K27me3 水平可以提高 CRC 患者的药物敏感性。
