TSP50 promotes the Warburg effect and hepatocyte proliferation via regulating PKM2 acetylation

Cell Death Dis. 2021 May 20;12(6):517. doi: 10.1038/s41419-021-03782-w.

Abstract

Metabolic reprogramming is a hallmark of malignancy. Testes-specific protease 50 (TSP50), a newly identified oncogene, has been shown to play an important role in tumorigenesis. However, its role in tumor cell metabolism remains unclear. To investigate this issue, LC-MS/MS was employed to identify TSP50-binding proteins and pyruvate kinase M2 isoform (PKM2), a known key enzyme of aerobic glycolysis, was identified as a novel binding partner of TSP50. Further studies suggested that TSP50 promoted aerobic glycolysis in HCC cells by maintaining low pyruvate kinase activity of the PKM2. Mechanistically, TSP50 promoted the Warburg effect by increasing PKM2 K433 acetylation level and PKM2 acetylation site (K433R) mutation remarkably abrogated the TSP50-induced aerobic glycolysis, cell proliferation in vitro and tumor formation in vivo. Our findings indicate that TSP50-mediated low PKM2 pyruvate kinase activity is an important determinant for Warburg effect in HCC cells and provide a mechanistic link between TSP50 and tumor metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Biomarkers, Tumor
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Female
  • HEK293 Cells
  • Hepatocytes / cytology
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Heterografts
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncogenes
  • Serine Endopeptidases / metabolism*
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / metabolism*
  • Transfection
  • Warburg Effect, Oncologic

Substances

  • Biomarkers, Tumor
  • Carrier Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • Serine Endopeptidases
  • testis-specific protease 50