PRMT1通过调控PKM2/PKM1比率促进沃伯格效应在非小细胞肺癌中的作用
PRMT1 promotes Warburg effect by regulating the PKM2/PKM1 ratio in non-small cell lung cancer
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影响因子:9.6
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
DOI:
10.1038/s41419-024-06898-x
摘要
异常的表观遗传修饰参与调节肿瘤细胞中的沃伯格效应。蛋白精氨酸甲基转移酶（PRMTs）介导精氨酸甲基化，在细胞反应中具有关键作用。PRMTs在多种癌症中表达失调，但其在癌症沃伯格效应中的具体作用尚不清楚。本研究的实验显示，PRMT1在葡萄糖充足条件下表达水平较高。PRMT1通过上调PTBP1，增加PKM2/PKM1的比率，促进非小细胞肺癌（NSCLC）中的有氧糖酵解。在p53缺失和突变的NSCLC中，PRMT1水平基本保持不变，而在p53野生型NSCLC中，葡萄糖不足条件下PRMT1的表达则有所下降。值得注意的是，在葡萄糖缺乏条件下，p53的激活可以抑制USP7，进而加速PRMT1的多泛素依赖性降解。褪黑激素是一种抑制葡萄糖摄取的激素，显著抑制p53野生型NSCLC的细胞增殖，而褪黑激素与USP7抑制剂P5091的联合应用增强了对p53缺失NSCLC的抗癌作用。我们的研究结果支持PRMT1在调控NSCLC沃伯格效应中的作用。此外，联合使用褪黑激素和USP7抑制剂显示出良好的疗效，为开发基于PRMT1的治疗策略以改善p53缺失NSCLC的预后提供了理论基础。
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.