O-GlcNAcylation Regulates Cancer Metabolism and Survival Stress Signaling via Regulation of the HIF-1 Pathway

Abstract

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.

Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase

“…A growing body of evidence demonstrates that O-GlcNAcylation occurs in response to diverse forms of damaging agents resulting from normal metabolic processes, as well as environmental factors, suggesting that O-GlcNAc modifications of protein is a component of the stress response program in cells [9,[55][56][57][58]. For instance, oxidative stress induced by hydrogen peroxide treatment leads to increased FOXO4 O-GlcNAcylation and enhanced transcriptional activity [59].…”

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

“…This protection is associated with decreased expression of proteins involved in the ER stress maladaptive response, including the folding enzyme chaperones Grp74 and Grp90 and CHOP (CCAAT/enhancer-binding protein homologous protein) (71). Indeed, it has been shown that reduction of hyper-OGlcNAcylation in cancer induces metabolic stress, thereby activating the CHOP/Bim pathway (38). Therefore, hyper-O-GlcNAcylation could contribute to cancer cell survival by mitigating ER stress through the inhibition of CHOP.…”

“…It has been reported that elevated OGlcNAcylation in cancer cells stabilizes HIF-1␣, thereby promoting the Warburg effect. Conversely, reduction of hyper-O-GlcNAcylation reverses cancer cell aerobic glycolysis to oxidative phosphorylation (38). Moreover, carbohydrate-responsive element-binding protein (ChREBP) contributes to metabolic reprogramming in tumors through inhibition of mitochondrial respiration and up-regulation of aerobic glycolysis, de novo lipogenesis, and nucleotide biosynthesis (39).…”

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis

“…cancers (16,19,20), but neither has been examined previously in the context of HPV oncogene expression or cervical neoplasms. In this work, we asked whether O-GlcNAc might play a role in HPVinduced transformation and carcinogenesis.…”