O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency

Abstract

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.

Upregulation of ZNF148 in SDHB‐deficient gastrointestinal stromal tumor potentiates Forkhead box M1‐mediated transcription and promotes tumor cell invasion

“…Dysfunction of metabolic enzymes has a fundamental effect on multiple cellular events, including DNA repair and gene transcription 21,22 . The physiological effect of SDHB deficiency observed in the present study exemplifies a concrete mechanistic linkage between SDHB metabolic activity and non–metabolic oncogenic signaling and GIST malignancy.…”

The impact of cellular metabolism on chromatin dynamics and epigenetics

“…A recent report demonstrated that loss-of-function mutations in FH and the subsequent accumulation of fumarate promotes epithelial-to-mesenchymal-transition (EMT) through fumarate-dependent inhibition of TET demethylases and subsequent induction of genes necessary for EMT 109 . FH was also found to be O-GlcNAcylated, which caused changes in histone methylation 110 , and provides evidence for additional layers of metabolic regulation of chromatin. Indeed a recent study proposed that a substantial portion of variation in DNA methylation profiles across all human cancers could be explained by differences in the expression of enzymes related to methionine and the one carbon network 111 .…”

Association of serum levels of antibodies against ALDOA and FH4 with transient ischemic attack and cerebral infarction

“…found that FH could antagonize α-ketoglutarate-dependent demethylase through its metabolite fumarate, thereby affecting histone methylation [49]. In addition, Wang et al also showed that FH exhibited adenosine monophosphate-activated protein kinase-mediated phosphorylation in the absence of glucose or hypoxia, which inhibited histone's demethylation by lysine-specific demethylase 2A [50]. FH inhibits histone methylation by reducing the physiological activity of vascular endothelial growth factor (VEGF) [51].…”