Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Mol Cell. 2014 Jun 5;54(5):820-31. doi: 10.1016/j.molcel.2014.04.026. Epub 2014 May 22.
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.
己糖胺生物合成途径可增加细胞内蛋白质的 O 连接 β-N-乙酰氨基葡萄糖（O-GlcNAc）的翻译后添加。癌细胞通过增加 O-连接 N-乙酰氨基葡萄糖转移酶（OGT）和/或降低 O-连接 N-乙酰氨基葡萄糖苷酶（OGA）水平来提高总 O-GlcNAcylation。降低 O-GlcNAcylation 可抑制致癌作用。在这里，我们证明 O-GlcNAcylation 通过缺氧诱导因子 1（HIF-1α）及其转录靶标 GLUT1 来调节癌细胞中的糖酵解。降低 O-GlcNAcylation 会增加α-酮戊二酸、HIF-1 羟化和与 von Hippel-Lindau 蛋白（pVHL）的相互作用，导致 HIF-1α 降解。降低癌细胞中的 O-GlcNAcylation 会导致内质网（ER）应激和通过 C/EBP 同源蛋白（CHOP）介导的癌细胞凋亡激活。HIF-1α 和 GLUT1 是 OGT 介导的代谢应激调节的关键，因为稳定的 HIF-1 或 GLUT1 的过表达可挽救代谢缺陷。具有高 HIF-1α 水平的人类乳腺癌含有升高的 OGT，而 OGA 水平的降低与不良的患者预后独立相关。因此，O-GlcNAcylation 通过调节 HIF-1α 来调节癌细胞代谢重编程和存活应激信号。
