O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency
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ABSTRACT: Chromatin-associated fumarase (FH) affects histone methylation via its metabolic activity. However, whether this regulation is implicated in gene transcription remains to be clarified. In this study, we show that glucose deprivation induces AMPK-dependent phosphorylation of FH at Ser 75, which promotes association of FH with transcriptional factor ATF2 and related gene promoters. The inhibitory effect of local fumarate on KDM2A histone demethylase maintains H3K36me2, thus facilitates transcription 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 the robust OGT activity. Consistently, FH-S75 phosphorylation levels inversely correlate with the OGT level and poor prognosis in pancreatic cancer patients. These findings uncover a mechanism underlying transcription regulation by metabolic enzyme and the linkage between dysregulated OGT activity and growth advantage of cancer cells under nutrient stress.
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: Yuhui Jiang
PROVIDER: MSV000080872 | MassIVE | Sat Apr 01 03:58:00 BST 2017
SECONDARY ACCESSION(S): PXD006229
REPOSITORIES: MassIVE
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