PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism  

作　　者：Mingming Sun Leilei Li Yujia Niu Yingzhi Wang Qi Yan Fei Xie Yaya Qiao Jiaqi Song Huanran Sun Zhen Li Sizhen Lai Hongkai Chang Han Zhang Jiyan Wang Chenxin Yang Huifang Zhao Junzhen Tan Yanping Li Shuangping Liu Bin Lu Min Liu Guangyao Kong Yujun Zhao Chunze Zhang Shu-Hai Lin Cheng Luo Shuai Zhang Changliang Shan 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,Nankai University,Tianjin 300350,China [2]Biomedical Translational Research Institute,Jinan University,Guangzhou 510632,China [3]State Key Laboratory of Cellular Stress Biology,Innovation Center for Cell Signaling Network,School of Life Sciences,Xiamen University,Xiamen 361102,China [4]School of Integrative Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China [5]Department of Pathology and Institute of Precision Medicine,Jining Medical University,Jining 272067,China [6]Department of Pathology,Medical School,Dalian University,Dalian 116622,China [7]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Hengyang Medical School,University of South China,Hengyang 421001,China [8]School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou 325035,China [9]Institute of Biomedical Sciences,Shandong Provincial Key Laboratory of Animal Resistance Biology,Collaborative Innovation Center of Cell Biology in Universities of Shandong,College of Life Sciences,Shandong Normal University,Jinan 250014,China [10]National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy,the Second Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710004,China [11]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [12]Department of Colorectal Surgery,Tianjin Union Medical Center Nankai University,Tianjin 300121,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期157-173,共17页药学学报（英文版）

基　　金：supported by grants from the Natural Science Foundation of Tianjin(21JCZDJC00060,China);the National Nature Science Foundation of China(81973356,91957120,81902826,and 81672781);the Fundamental Research Funds for the Central Universities of Nankai University(3206054,91923101,63213082 and 92122017,China);the State Key Laboratory of Drug Research(SIMM2105KF-08,China);the National Key R&D Program of China(No.2018YFC2002000);the Innovative S&T Projects for Young Researchers of Tianjin Academy of Agricultural Science(grant No.201918,China);the Natural Science Foundation of Tianjin(19JCYBJC29600 and 21JCYBJC00180,China)。

摘　　要：Metabolic reprogramming is a hallmark of cancer,including lung cancer.However,the exact underlying mechanism and therapeutic potential are largely unknown.Here we report that protein arginine methyltransferase 6(PRMT6)is highly expressed in lung cancer and is required for cell metabolism,tumorigenicity,and cisplatin response of lung cancer.PRMT6 regulated the oxidative pentose phosphate pathway(PPP)flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phosphogluconate dehydrogenase(6PGD)and a-enolase(ENO1).Furthermore,PRMT6 methylated R324 of 6PGD to enhancing its activity;while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate(2-PG)binding to ENO1,respectively.Lastly,targeting PRMT6 blocked the oxidative PPP flux,glycolysis pathway,and tumor growth,as well as enhanced the antitumor effects of cisplatin in lung cancer.Together,this study demonstrates that PRMT6 acts as a posttranslational modification(PTM)regulator of glucose metabolism,which leads to the pathogenesis of lung cancer.It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

关 键 词：Lung cancer Metabolic reprogramming Post-translational modification PRMT6 Pentose phosphate pathway flux GLYCOLYSIS 6-Phospho-gluconate dehydrogenase a-enolase ENO1 

分 类 号：R730.5[医药卫生—肿瘤]