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

Abstract

BackgroundCancer 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 clinical significance of PGK1 expression and function in cancer progression is unclear. Here, we investigated the relationship between the progression and prognosis of multiple cancer types and PGK1 expression and its function in the mitochondrial metabolism regulation.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.

Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

“…Accordingly, PTMs play vital roles in regulating the function of PGK-1 during tumorigenesis. More specifically, promoter methylation has been negatively associated with the mRNA expression of PGK-1; phosphorylation of the PGK-1 protein was associated with the clinical outcomes of PDAC patients [144].…”

“…Phosphoglycerate kinase (PGK), as the first enzyme in glycolysis that produces ATP, includes two forms of PGK, the extensively expressed form PGK-1 and the testis-expressed form PGK-2. It has been demonstrated by immunohistochemistry that PGK-1 is highly expressed in PDAC [ 144 ]. Interestingly, PGK-1 has been proven to affect DNA duplication and repair in the mammalian nucleus.…”

“…Accordingly, PTMs play vital roles in regulating the function of PGK-1 during tumorigenesis. More specifically, promoter methylation has been negatively associated with the mRNA expression of PGK-1; phosphorylation of the PGK-1 protein was associated with the clinical outcomes of PDAC patients [ 144 ]. Interestingly, another study reported that pyruvate dehydrogenase kinase 1 (PDHK-1) is phosphorylated by mitochondria-translocated PGK-1 (acting as a protein kinase), which activates PDHK-1 and augments glycolysis but inhibits OXPHOS [ 146 ].…”

Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell‑like properties and the epithelial‑mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway

“…PGK1 expression in several tumour tissues was found to be higher compared with that in normal tissues ( 26 ), whilst HIF-1α has been previously shown to directly regulate PGK1 ( 52 ). In liver cancer, the expression levels of PGK1 and HIF-1α in the hepatocellular carcinoma cell line HCCLM9 with high metastasis were higher when compared with those in the hepatocellular carcinoma cell line MHCC97L with low metastasis ( 26 , 33 ), such that PGK1 has also been revealed to regulate cell proliferation and metastasis ( 32 ). In addition, PGK1 expression was found to correlate with the survival and prognosis of patients with breast cancer ( 53 ).…”

Proteomics analysis reveals alterations of NK cells in patients with severe aplastic anemia

“…PGK1 is an important enzyme in the metabolic glycolysis pathway. It not only generates a molecule of ATP, but also controls and induces tumorgenesis in many cancers . ARP2/3 is essential for neuronal cell differentiation and maturation .…”