PRMT1通过调节非小细胞肺癌的PKM2/PKM1比来促进沃伯格效应
PRMT1 promotes Warburg effect by regulating the PKM2/PKM1 ratio in non-small cell lung cancer
影响因子:9.60000
分区:生物学1区 Top / 细胞生物学2区
发表日期:2024 Jul 15
作者:
Lu Peng, Yujiao Zhao, Jiang Tan, Jingyao Hou, Xin Jin, Dong-Xu Liu, Baiqu Huang, Jun Lu
摘要
肿瘤细胞中沃堡效应的调节涉及异常表观遗传修饰。蛋白精氨酸甲基转移酶（PRMTS）介导精氨酸甲基化，并在细胞反应中具有关键功能。 PRMT在各种癌症中被放松，但是它们在沃尔堡效应中的精确作用在很大程度上是未知的。当前研究的实验表明，在葡萄糖足够的条件下，PRMT1高度表达。 PRMT1通过上调PTBP1引起了PKM2/PKM1比率的增加，进而促进非小细胞肺癌（NSCLC）中的有氧糖酵解。在葡萄糖不足的条件下，p53缺陷型和p53损坏的NSCLC中的PRMT1水平保持相对不变。值得注意的是，在缺乏葡萄糖的条件下的p53激活可以抑制USP7，并进一步加速PRMT1的多泛素依赖性降解。褪黑激素是一种抑制葡萄糖摄入的激素，显着抑制了p53野生型NSCLC的细胞增殖，而褪黑激素和USP7抑制剂p5091的组合增强了p53缺乏NSCLC的抗癌活性。我们的集体发现支持PRMT1在NSCLC中Warburg效应的调节中的作用。此外，使用褪黑激素和USP7抑制剂的联合治疗表现出良好的疗效，这为开发基于PRMT1的治疗以改善p53缺陷型NSCLC结果提供了理由。
Abstract
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.