O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.
O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.
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DOI：
10.1016/j.molcel.2014.04.026
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发表时间：
2014-06-05
期刊：
影响因子：
16
通讯作者：
Reginato, Mauricio J.
中科院分区：
文献类型：
--
作者：
Ferrer, Christina M.;Lynch, Thomas P.;Sodi, Valerie L.;Falcone, John N.;Schwab, Luciana P.;Peacock, Danielle L.;Vocadlo, David J.;Seagroves, Tiffany N.;Reginato, Mauricio J.
己糖胺生物合成途径导致细胞内蛋白质上O-连接-β N-乙酰葡糖胺（O-GlcNAc）的翻译后加成增加。癌细胞通过增加O-GlcNAc转移酶（OGT）和/或降低O-GlcNAcase（OGA）水平来提高总O-GlcNAcylation。减少癌细胞中的O-GlcNAc化可抑制肿瘤发生。在这里，我们证明了O-GlcNAc化通过HIF-1α及其转录靶点GLUT 1调节癌细胞中的糖酵解。减少O-GlcNAc酰化增加α-酮戊二酸、HIF-1羟基化和与VHL的相互作用，导致HIF-1α降解。减少癌细胞中的O-GlcNAc化导致ER应激的激活和通过BCL 2家族蛋白的CHOP诱导介导的癌细胞凋亡。HIF-1α和GLUT 1对于OGT介导的代谢应激调节至关重要，因为稳定的HIF-1或GLUT 1的过表达挽救了代谢缺陷和细胞凋亡。具有高水平HIF-1α的人基底样乳腺癌含有升高的OGT、O-GlcNAc化和较低的OGA水平，这些与患者预后不良独立相关。因此，O-GlcNAc化通过调节HIF-1α来调节癌细胞代谢重编程和存活应激信号传导。
The Hexosamine Biosynthetic Pathway leads to elevated post-translation addition of O-linked-βN-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 in cancer cells inhibits oncogenesis. Here, we demonstrate that O-GlcNAcylation regulates glycolysis in cancer cells via HIF-1α and its transcriptional target GLUT1. Reducing O-GlcNAcylation increases α-ketoglutarate, HIF-1 hydroxylation and interaction with VHL resulting in HIF-1α degradation. Reducing O-GlcNAcylation in cancer cells results in activation of ER stress and apoptosis of cancer cells mediated through CHOP induction of BCL2-family proteins. HIF-1α and GLUT1 are critical for OGT-mediated regulation of metabolic stress as overexpression of stable HIF-1 or GLUT1 rescues metabolic defects and apoptosis. Human basal-like breast cancers with high levels of HIF-1α contain elevated OGT, O-GlcNAcylation 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.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
在癌细胞代谢中解码关键节点：糖和香料以及所有事物。
DOI：
10.3410/b4-2
发表时间：
2012
期刊：
F1000 biology reports
影响因子：
--
作者：
Shaw RJ;Cantley LC
通讯作者：
Cantley LC
影响因子：
4.6
作者：
Krzeslak, Anna;Forma, Ewa;Bernaciak, Magdalena;Romanowicz, Hanna;Brys, Magdalena
通讯作者：
Brys, Magdalena
影响因子：
64.5
作者：
Dennis JW;Nabi IR;Demetriou M
通讯作者：
Demetriou M
影响因子：
5.3
作者：
O'Donnell, N;Zachara, NE;Marth, JD
通讯作者：
Marth, JD