生物
内质网
癌细胞
细胞生物学
癌变
癌症研究
过剩1
信号转导
下调和上调
未折叠蛋白反应
癌症
生物化学
葡萄糖摄取
内分泌学
基因
遗传学
胰岛素
作者
Christina M. Ferrer,Thomas P. Lynch,Valerie L. Sodi,John N. Falcone,Luciana P. Schwab,Danielle L. Peacock,David J. Vocadlo,Tiffany N. Seagroves,Mauricio J. Reginato
出处
期刊:Molecular Cell
[Elsevier]
日期:2014-06-01
卷期号:54 (5): 820-831
被引量:310
标识
DOI:10.1016/j.molcel.2014.04.026
摘要
The hexosamine biosynthetic pathway elevates posttranslational addition of O-linked β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. Cancer cells elevate total O-GlcNAcylation by increasing O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels. Reducing O-GlcNAcylation inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via hypoxia-inducible factor 1 (HIF-1α) and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation, and interaction with von Hippel-Lindau protein (pVHL), resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of endoplasmic reticulum (ER) stress and cancer cell apoptosis mediated through C/EBP homologous protein (CHOP). HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress, as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects. Human breast cancers with high levels of HIF-1α contain elevated OGT, and lower OGA levels correlate independently with poor patient outcome. Thus, O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α.
科研通智能强力驱动
Strongly Powered by AbleSci AI