Deng Hong, Xu Qin, Zhang Qiang, Liu Chunfeng, Ren Lei
Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China, CN.
Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China, CN.
Biochem J. 2025 May 2;482(10):569-81. doi: 10.1042/BCJ20240607.
Colorectal cancer (CRC) is characterized by aggressive tumor growth and chemoresistance, with Enhancer of zeste homolog 2 (EZH2) serving a pivotal role in these processes. However, the mechanisms by which it drives tumor proliferation and therapeutic resistance through autophagy regulation remain unclear. Here, we demonstrated that EZH2 expression is elevated in CRC tissues and cell lines, correlating with chemoresistance and diagnostic potential (Area Under the Curve, AUC = 0.968). EZH2 knockdown markedly reduced CRC cell proliferation, while its overexpression promoted tumor growth and increased resistance to irinotecan. Mechanistically, EZH2 suppressed autophagy in CRC cells, a process linked to chemosensitivity, by directly regulating LC3bI/II expression. Notably, EZH2 enhanced the Neuropilin-1 (NRP1) level by binding to the NRP1 promoter, thereby promoting tumor proliferation and irinotecan resistance through autophagy inhibition. NRP1 depletion partially reversed these effects, underscoring the crucial role of the EZH2-NRP1 axis in CRC. Our findings highlight that targeting the EZH2-NRP1 interaction could represent a novel therapeutic approach to overcoming chemoresistance in CRC.
结直肠癌（CRC）的特征是肿瘤生长侵袭性强且具有化学抗性，zeste同源物2增强子（EZH2）在这些过程中起关键作用。然而，其通过自噬调节驱动肿瘤增殖和治疗抗性的机制仍不清楚。在此，我们证明EZH2在CRC组织和细胞系中的表达升高，与化学抗性和诊断潜力相关（曲线下面积，AUC = 0.968）。EZH2敲低显著降低了CRC细胞增殖，而其过表达促进肿瘤生长并增加对伊立替康的抗性。机制上，EZH2通过直接调节LC3bI/II表达抑制CRC细胞中的自噬，这一过程与化学敏感性相关。值得注意的是，EZH2通过与Neuropilin-1（NRP1）启动子结合提高NRP1水平，从而通过自噬抑制促进肿瘤增殖和伊立替康抗性。NRP1缺失部分逆转了这些效应，强调了EZH2-NRP1轴在CRC中的关键作用。我们的研究结果突出表明，靶向EZH2-NRP1相互作用可能代表一种克服CRC化学抗性的新型治疗方法。
