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

Christina M. Ferrer, Thomas P. Lynch, Valerie L. Sodi, John N. Falcone, Luciana P. Schwab, Danielle L. Peacock, David J. Vocadlo, Tiffany N. Seagroves, and Mauricio J. Reginato

Molecular Cell. 2014 Jun 5;54(5):820-31.

Speaker: Yi-Hsin, Hsiao (蕭宜馨)                         Time: 15:00~16:00, Dec 10, 2014.

Commentator: Dr. Chuan-Fa, Chang (張權發 老師)          Place: Room 601

Abstract:

O-GlcNAcylation is a dynamic protein modification abundant within the cancer cells. The O-GlcNAc transferase (OGT) attaches O-Linked β-N-acetylglucosamine (O-GlcNAc) to proteins at specific serine or threonine residues. Contrary to OGT, O-GlcNAcase hydrolyzes O-GlcNAc from proteins. The phenomena Warburg effect, aberrant glucose metabolism characterized by aerobic glycolysis; therefore, the enhanced glucose and glutamine uptake in cancer cells resulting in certain metabolism hexosamine biosynthetic pathway (HBP). Especially, UDP-N-acetylglucosamine (UDP-GlcNAc), the end product of the HBP, is the donor of OGT which induce the high level of O-GlcNAcylation. The author showed that OGT is a new target in various cancer cells such as lung cancer, prostate cancer and breast cancer in their previous studies. Hypoxia inducible transcription factors (HIFs) involved in the great part of cellular metabolism and diverse transcription including angiogenesis, proliferation, and migration that associated with oncogenesis and tumor progression. In this study, the author clarified the mechanism of O-GlcNAcylation regulate metabolic reprogramming via HIF-1within breast cancer cells. Initially, they screened the metabolite in elevated O-GlcNAcylation indeed tended the cancer cells to glycolysis pathway and activated themTOR pathway in breast cancer cells in OGT overexpression system. They found that reducing O-GlcNAcylation would increase HIF-1 hydroxylation and the interaction with von Hippel-Lindau protein (pVHL) lead to HIF-1αdegradation in OGT knockdown system. The decreasing OGT caused ER stress and CHOP-dependent apoptosis in cancer cells but not immortal epithelium cells. Further investigation in animal study revealed that the tumor size was inhibited by reduction of OGT; and, the addition of HIF-1 transcriptional target GLUT1 could rescue tumor regression induced by OGT knock down system. Data from patient study gave the information that there are high level OGT expression in breast cancer cells. In conclusion, OGT-targeted block may be the good therapeutics in numerous cancer cells.

References:

1.         Paweł Jó´zwiak, Ewa Forma, Magdalena Bry´s and Anna Krze´slak. O-GlcNAcylation and metabolic reprograming in cancer. Front Endocrinol (Lausanne). 2014 Sep 9;5:145.

2.         Wilson GK, Tennant DA, McKeating JA. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: Current understanding and future directions. J Hepatol. 2014 Aug 23. pii: S0168-8278(14)00612-6.