PGK1 Promoter Hypomethylation and PGK1-Mediated PDHK1 Phosphorylation Associate with Stage and Prognosis in Multiple Human Cancers

Background: Cancer cells reprogram metabolism for proliferation. Phosphoglycerate kinase 1 (PGK1), as an aerobic glycolytic enzyme and a protein kinase, coordinates glycolysis and mitochondrial metabolism in glioblastoma multiforme cells. However, the clinical significance of PGK1 in most types of cancer is largely unknown. Methods: We performed Pan-Cancer analyses of PGK1 mRNA expression and DNA methylation in 11,908 tumours and 1582 paired non-tumour tissues across 34 cancer types in The Cancer Genome Atlas datasets. Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry using tissue microarray assay in additional 818 independent cases with 550 paired normal tissues from 5 cancer types. Findings: PGK1 mRNA expression was significantly elevated in 15 cancer types with hypomethylation in the promotor regions (six cancer types), and was associated with advanced TNM stage in five cancer types. In breast carcinoma, both PGK1 high mRNA expression and promoter hypomethylation decreased survival. Kaplan-Meier analysis revealed that PGK1 S203 phosphorylation was correlated with downstream PDHK1 T338 phosphorylation positively and poor survival in cancers of the breast (n=145, P=.038), liver (n=185, P=.001), lung (n=179, P=.002), stomach (n=95, P=.005), and esophagus (n=214, P=.006). Multivariate Cox regression model showed that PGK1 S203 and PDHK1 T338 phosphorylation were independent predictors of poor survival in liver, lung, and stomach cancer. Interpretation: Our study linked elevated PGK1 expression, PGK1 promoter hypomethylation and activating PGK1 S203 and PDHK1 T338 phosphorylation to progression and poor survival in diverse types of cancer, and highlighted the potential of PGK1 phosphorylation as prognostic biomarkers in cancer. Funding: National Key R&D Program of China (2017YFC1308702, 2017YFC1311003), Beijing Municipal Science & Technology Commission (Z181100001918002), CAMS Initiative for Innovative Medicine (2017-I2M-1-005), and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32001). Declaration of Interest: The authors declare that there are no potential conflicts of interest. Ethical Approval: This study was approved by the Institute Research Medical Ethics Committee of the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital in Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing.