Ma Q, Jiang H, Ma L, Zhao G, Xu Q, Guo D, He N, Liu H, Meng Z, Liu J, Zhu L, Lin Q, Wu X, Li M, Luo S, Fang J, Lu Z

Aberrantly upregulated choline phospholipid metabolism is a novel emerging hallmark of cancer, and choline kinase ? (CHK?), a key enzyme for phosphatidylcholine production, is overexpressed in many types of human cancer through undefined mechanisms. Here, we demonstrate that the expression levels of the glycolytic enzyme enolase-1 (ENO1) are positively correlated ...

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with CHK? expression levels in human glioblastoma specimens and that ENO1 tightly governs CHK? expression via posttranslational regulation. Mechanistically, we reveal that both ENO1 and the ubiquitin E3 ligase TRIM25 are associated with CHK?. Highly expressed ENO1 in tumor cells binds to I199/F200 of CHK?, thereby abrogating the interaction between CHK? and TRIM25. This abrogation leads to the inhibition of TRIM25-mediated polyubiquitylation of CHK? at K195, increased stability of CHK?, enhanced choline metabolism in glioblastoma cells, and accelerated brain tumor growth. In addition, the expression levels of both ENO1 and CHK? are associated with poor prognosis in glioblastoma patients. These findings highlight a critical moonlighting function of ENO1 in choline phospholipid metabolism and provide unprecedented insight into the integrated regulation of cancer metabolism by crosstalk between glycolytic and lipidic enzymes.

Date: Apr. 11, 2023

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