O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency

Nat Cell Biol. 2017 Jul;19(7):833-843. doi: 10.1038/ncb3562. Epub 2017 Jun 19.


Chromatin-associated fumarase (FH) affects histone methylation via its metabolic activity. However, whether this effect is involved in gene transcription remains to be clarified. In this study, we show that under glucose deprivation conditions, AMPK phosphorylates FH at Ser75, which in turn forms a complex with ATF2 and participates in promoter activation. FH-catalysed fumarate in promoter regions inhibits KDM2A demethylase activity, and thus maintains the H3K36me2 profile and facilitates gene expression for cell growth arrest. On the other hand, FH is found to be O-GlcNAcylated at the AMPK phosphorylation site; FH-ATF2-mediated downstream events are impeded by FH O-GlcNAcylation, especially in cancer cells that display robust O-GlcNAc transferase (OGT) activity. Consistently, the FH-Ser75 phosphorylation level inversely correlates with the OGT level and poor prognosis in pancreatic cancer patients. These findings uncover a previously uncharacterized mechanism underlying transcription regulation by FH and the linkage between dysregulated OGT activity and growth advantage of cancer cells under glucose deficiency.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Activating Transcription Factor 2 / genetics
  • Activating Transcription Factor 2 / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation*
  • DNA Methylation
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • Fumarate Hydratase / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glucose / deficiency*
  • Glycosylation
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Male
  • Mice, Nude
  • Multiprotein Complexes
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Interference
  • Time Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Burden


  • ATF2 protein, human
  • Activating Transcription Factor 2
  • F-Box Proteins
  • Multiprotein Complexes
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • AMP-Activated Protein Kinases
  • Fumarate Hydratase
  • Glucose