Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi 117004, China.
Sci Adv. 2023 Jun 2;9(22):eadc9273. doi: 10.1126/sciadv.adc9273. Epub 2023 May 31.
Lung cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic enzyme mutations are closely related to the malignant phenotype of lung cancer. Here, we identified a series of gain-of-function mutations in the histone methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic enzyme and provide promising insights for the precise treatment of lung cancer patients.
肺癌是一种致命的恶性肿瘤，缺乏有效的治疗方法。新出现的证据表明，表观遗传酶突变与肺癌的恶性表型密切相关。在这里，我们鉴定了一系列组蛋白甲基转移酶 DOT1L 的功能获得性突变。其中最强的是位于催化 DOT 结构域的 R231Q。R231Q 可以增强 DOT1L 的底物结合能力。此外，R231Q 促进了肺癌细胞在体外和体内的生长和耐药性。机制研究还表明，R231Q 突变通过在启动子上富集 H3K79me2，并通过表观遗传调控下游靶基因的表达，特异性地激活 MAPK/ERK 信号通路。DOT1L 抑制剂（SGC0946）和 MAPK/ERK 轴抑制剂（binimetinib）的联合使用可以有效地逆转 R231Q 诱导的现象。我们的研究结果揭示了表观遗传酶的功能获得性突变，并为肺癌患者的精准治疗提供了有前景的思路。
