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O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency

Ting Wang1,2, Qiujing Yu1, Jingjie Li1

  • 1The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, China.

Nature Cell Biology
|June 20, 2017
PubMed

Insights

Chromatin-associated fumarase (FH) regulates gene transcription by influencing histone methylation under glucose deprivation. Dysregulated O-GlcNAcylation of FH, particularly in cancer cells, impedes this process, correlating with poor prognosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Chromatin-associated fumarase (FH) impacts histone methylation through its metabolic functions.
  • The precise role of FH in gene transcription regulation requires further elucidation.

Purpose of the Study:

  • To investigate the mechanism by which FH influences gene transcription under glucose deprivation.
  • To explore the interplay between FH phosphorylation, O-GlcNAcylation, and cancer cell growth.

Main Methods:

  • Investigated the interaction between AMPK, FH, and ATF2 under glucose-limited conditions.
  • Assessed the impact of FH-catalyzed fumarate on KDM2A demethylase activity and H3K36me2 levels.
  • Analyzed FH O-GlcNAcylation and its effect on FH-ATF2 complex formation.
  • Correlated FH phosphorylation and O-GlcNAcylation levels with OGT activity and patient prognosis in pancreatic cancer.

Main Results:

  • AMP-activated protein kinase (AMPK) phosphorylates FH at Ser75 under glucose deprivation, promoting promoter activation via an FH-ATF2 complex.
  • FH-derived fumarate inhibits KDM2A, maintaining H3K36me2 and facilitating gene expression for cell growth arrest.
  • FH O-GlcNAcylation at Ser75 impedes FH-ATF2 complex formation and downstream transcriptional regulation, especially in cancer cells with high O-GlcNAc transferase (OGT) activity.
  • FH-Ser75 phosphorylation inversely correlates with OGT levels and predicts poor prognosis in pancreatic cancer.

Conclusions:

  • Uncovered a novel mechanism of transcriptional regulation by FH involving its metabolic activity and post-translational modifications.
  • Demonstrated a link between dysregulated OGT activity, FH modification, and cancer cell proliferation advantage under nutrient stress.
  • FH phosphorylation and O-GlcNAcylation represent potential therapeutic targets in cancer treatment.

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