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.
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.
染色质相关的富马酸酶（FH）通过其代谢活性影响组蛋白甲基化。然而，这种影响是否涉及基因转录仍有待阐明。在这项研究中，我们表明在葡萄糖剥夺条件下，AMPK 在 FH 的丝氨酸 75 位磷酸化，进而与 ATF2 形成复合物并参与启动子激活。FH 在启动子区域催化的富马酸抑制 KDM2A 去甲基酶的活性，从而维持 H3K36me2 谱并促进细胞生长停滞的基因表达。另一方面，FH 在 AMPK 磷酸化位点被 O-GlcNAc 化；FH-ATF2 介导的下游事件被 FH-O-GlcNAc 化所阻碍，特别是在具有强 O-GlcNAc 转移酶（OGT）活性的癌细胞中。一致地，FH-Ser75 磷酸化水平与 OGT 水平呈负相关，并且与胰腺癌患者的预后不良相关。这些发现揭示了 FH 转录调控的一个以前未被描述的机制，以及在葡萄糖缺乏下，失调的 OGT 活性与癌细胞生长优势之间的联系。
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