柠檬酸循环
丙酮酸脱氢酶复合物
糖酵解
瓦博格效应
结直肠癌
丙酮酸脱氢酶激酶
巴基斯坦卢比
新陈代谢
生物化学
化学
丙酮酸激酶
癌症研究
分子生物学
生物
遗传学
酶
癌症
作者
Huijuan Wang,Jie Sun,Haofan Sun,Yifei Wang,Bingyi Lin,Liming Wu,Weijie Qin,Qiong Zhu,Wen Yi
标识
DOI:10.1038/s41418-024-01315-4
摘要
Abstract Deregulated glucose metabolism termed the “Warburg effect” is a fundamental feature of cancers, including the colorectal cancer. This is typically characterized with an increased rate of glycolysis, and a concomitant reduced rate of the tricarboxylic acid (TCA) cycle metabolism as compared to the normal cells. How the TCA cycle is manipulated in cancer cells remains unknown. Here, we show that O -linked N -acetylglucosamine (O-GlcNAc) regulates the TCA cycle in colorectal cancer cells. Depletion of OGT, the sole transferase of O-GlcNAc, significantly increases the TCA cycle metabolism in colorectal cancer cells. Mechanistically, OGT-catalyzed O-GlcNAc modification of c-Myc at serine 415 (S415) increases c-Myc stability, which transcriptionally upregulates the expression of pyruvate dehydrogenase kinase 2 (PDK2). PDK2 phosphorylates pyruvate dehydrogenase (PDH) to inhibit the activity of mitochondrial pyruvate dehydrogenase complex, which reduces mitochondrial pyruvate metabolism, suppresses reactive oxygen species production, and promotes xenograft tumor growth. Furthermore, c-Myc S415 glycosylation levels positively correlate with PDK2 expression levels in clinical colorectal tumor tissues. This study highlights the OGT–c-Myc–PDK2 axis as a key mechanism linking oncoprotein activation with deregulated glucose metabolism in colorectal cancer.
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