The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China.
The Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China.
Cell Death Dis. 2024 Jul 15;15(7):504. doi: 10.1038/s41419-024-06898-x.
Abnormal epigenetic modifications are involved in the regulation of Warburg effect in tumor cells. Protein arginine methyltransferases (PRMTs) mediate arginine methylation and have critical functions in cellular responses. PRMTs are deregulated in a variety of cancers, but their precise roles in Warburg effect in cancer is largely unknown. Experiments from the current study showed that PRMT1 was highly expressed under conditions of glucose sufficiency. PRMT1 induced an increase in the PKM2/PKM1 ratio through upregulation of PTBP1, in turn, promoting aerobic glycolysis in non-small cell lung cancer (NSCLC). The PRMT1 level in p53-deficient and p53-mutated NSCLC remained relatively unchanged while the expression was reduced in p53 wild-type NSCLC under conditions of glucose insufficiency. Notably, p53 activation under glucose-deficient conditions could suppress USP7 and further accelerate the polyubiquitin-dependent degradation of PRMT1. Melatonin, a hormone that inhibits glucose intake, markedly suppressed cell proliferation of p53 wild-type NSCLC, while a combination of melatonin and the USP7 inhibitor P5091 enhanced the anticancer activity in p53-deficient NSCLC. Our collective findings support a role of PRMT1 in the regulation of Warburg effect in NSCLC. Moreover, combination treatment with melatonin and the USP7 inhibitor showed good efficacy, providing a rationale for the development of PRMT1-based therapy to improve p53-deficient NSCLC outcomes.
异常的表观遗传修饰参与了肿瘤细胞中瓦博格效应的调节。精氨酸甲基转移酶（PRMTs）介导精氨酸甲基化，在细胞反应中具有关键作用。PRMTs 在多种癌症中失调，但它们在癌症瓦博格效应中的确切作用在很大程度上尚不清楚。本研究的实验表明，在葡萄糖充足的条件下，PRMT1 表达水平较高。PRMT1 通过上调 PTBP1 诱导 PKM2/PKM1 比值增加，进而促进非小细胞肺癌（NSCLC）的有氧糖酵解。在葡萄糖不足的条件下，p53 缺失和 p53 突变型 NSCLC 中的 PRMT1 水平相对不变，而在 p53 野生型 NSCLC 中的表达减少。值得注意的是，葡萄糖缺乏条件下 p53 的激活可以抑制 USP7，进一步加速 PRMT1 的多泛素依赖性降解。褪黑素是一种抑制葡萄糖摄取的激素，它显著抑制了 p53 野生型 NSCLC 的细胞增殖，而褪黑素和 USP7 抑制剂 P5091 的联合使用增强了 p53 缺失型 NSCLC 的抗癌活性。我们的研究结果支持 PRMT1 在 NSCLC 中调节瓦博格效应的作用。此外，褪黑素和 USP7 抑制剂的联合治疗显示出良好的疗效，为基于 PRMT1 的治疗方法的发展提供了依据，以改善 p53 缺失型 NSCLC 的预后。
