Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Cell Rep. 2024 Feb 27;43(2):113714. doi: 10.1016/j.celrep.2024.113714. Epub 2024 Feb 1.
Drug resistance is the leading problem in non-small-cell lung cancer (NSCLC) therapy. The contribution of histone methylation in mediating malignant phenotypes of NSCLC is well known. However, the role of histone methylation in NSCLC drug-resistance mechanisms remains unclear. Here, our data show that EZH2 and G9a, two histone methyltransferases, are involved in the drug resistance of NSCLC. Gene manipulation results indicate that the combination of EZH2 and G9a promotes tumor growth and mediates drug resistance in a complementary manner. Importantly, clinical study demonstrates that co-expression of both enzymes predicts a poor outcome in patients with NSCLC. Mechanistically, G9a and EZH2 interact and promote the silencing of the tumor-suppressor gene SMAD4, activating the ERK/c-Myc signaling pathway. Finally, SU08, a compound targeting both EZH2 and G9a, is demonstrated to sensitize resistant cells to therapeutic drugs by regulating the SMAD4/ERK/c-Myc signaling axis. These findings uncover the resistance mechanism and a strategy for reversing NSCLC drug resistance.
耐药性是治疗非小细胞肺癌（NSCLC）的主要问题。组蛋白甲基化在介导 NSCLC 恶性表型方面的作用已众所周知。然而，组蛋白甲基化在 NSCLC 耐药机制中的作用尚不清楚。在这里，我们的数据表明，两种组蛋白甲基转移酶 EZH2 和 G9a 参与了 NSCLC 的耐药性。基因操作结果表明，EZH2 和 G9a 的组合以互补的方式促进肿瘤生长并介导耐药性。重要的是，临床研究表明，两种酶的共表达预测 NSCLC 患者预后不良。从机制上讲，G9a 和 EZH2 相互作用并促进肿瘤抑制基因 SMAD4 的沉默，激活 ERK/c-Myc 信号通路。最后，实验表明，靶向 EZH2 和 G9a 的化合物 SU08 通过调节 SMAD4/ERK/c-Myc 信号轴，可增强耐药细胞对治疗药物的敏感性。这些发现揭示了 NSCLC 耐药性的耐药机制和逆转策略。
