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

O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency.

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The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200080, China.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China.


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.

[Indexed for MEDLINE]

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