Associations of PGK1 promoter hypomethylation and PGK1-mediated PDHK1 phosphorylation with cancer stage and prognosis:a TCGA pan-cancer analysis  

作　　者：Fei Shao Xueying Yang Wei Wang Juhong Wang Wei Guo Xiaoli Feng Susheng Shi Qi Xue Shugeng Gao Yibo Gao Zhimin Lu Jie He 

机构地区：[1]Department of Thoracic Surgery,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,No.17 Panjiayuannanli,Chaoyang District,Beijing 100021,P.R.China [2]Qingdao Cancer Institute,Cancer Institute of The Affiliated Hospital of Qingdao University,Qingdao 266003,Shandong,P.R.China [3]Zhejiang Provincial Key Laboratory of Pancreatic Disease,The First Affiliated Hospital,and Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,Zhejiang,P.R.China [4]Department of Pathology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,P.R.China [5]State Key Laboratory of Molecular Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,P.R.China

出　　处：《Cancer Communications》2019年第1期482-498,共17页癌症通讯（英文）

基　　金：This study was funded by The National Key R&D Program of China(2017YFC1308702,2017YFC1311000,2018YFC1312100);the Beijing Municipal Science&Technology Commission(Z181100006218032,Z181100001918002);the CAMS Initiative for Innovative Medicine(2017-I2M-1-005,2017-I2M-2-003,2019-I2M-2-002);Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2017PT32001,2017PT32017).

摘　　要：Background:Cancer cells reprogram metabolism for proliferation.Phosphoglycerate kinase 1(PGK1),as a glycolytic enzyme and newly identified protein kinase,coordinates glycolysis and mitochondrial metabolism.However,the clini-cal significance of PGK1 expression and function in cancer progression is unclear.Here,we investigated the relation-ship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.Methods:We performed pan-cancer analyses of PGK1 mRNA level and DNA methylation in 11,908 tumor tissues and 1582 paired normal tissues across 34 cancer types in The Cancer Genome Atlas datasets.Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation,we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.Results:The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types,respectively.In breast carcinoma,elevated PGK1 mRNA level and promoter hypomethylation were associated with poor prognosis.Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival(OS)in cancers of the breast,liver,lung,stomach,and esophagus and with advanced TNM stage in breast and esophageal cancers.PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver,lung,and stomach cancer.Conclusions:The elevated expression,promoter hypomethylation,and phosphorylation of PGK1 and PDHK1 were related with disease progression and short OS in diverse types of cancer.PGK1 and PDHK1 phosphorylation may be potential prognostic biomarkers.

关 键 词：PGK1 Cancer metabolism Epigenetics PHOSPHORYLATION Methylation The Cancer Genome Atlas Pan-cancer analysis PROGNOSIS Overall survival 

分 类 号：R73[医药卫生—肿瘤]