Transcription factor NFAT5 contributes to the glycolytic phenotype rewiring and pancreatic cancer progression via transcription of PGK1

Cell Death Dis. 2019 Dec 11;10(12):948. doi: 10.1038/s41419-019-2072-5.

Abstract

Hypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Aged
  • Animals
  • Carcinoma, Pancreatic Ductal / diagnostic imaging
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Proliferation / genetics
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Glycolysis / genetics
  • Heterografts
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Phenotype
  • Phosphoglycerate Kinase / genetics*
  • Positron Emission Tomography Computed Tomography
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction / genetics
  • Trans-Activators / genetics
  • Transcription Factors / genetics*
  • Transcription, Genetic*
  • Tumor Hypoxia / genetics
  • Tumor Microenvironment / genetics
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Homeodomain Proteins
  • KRAS protein, human
  • NFAT5 protein, human
  • TP53 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • pancreatic and duodenal homeobox 1 protein
  • PGK1 protein, human
  • Phosphoglycerate Kinase
  • Proto-Oncogene Proteins p21(ras)