Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

• Published in: Science (American Association for the Advancement of Science) 2012-08, Vol.337 (6097), p.975-980
• Main Authors: Yi, Wen, Clark, Peter M., Mason, Daniel E., Keenan, Marie C., Hill, Collin, Goddard, William A., Peters, Eric C., Driggers, Edward M., Hsieh-Wilson, Linda C.
• Format: Article
• Language: English
• Subjects: Acetylglucosamine - metabolism; Acylation; Adenosine Triphosphate - metabolism; Anaerobic conditions; Analytical, structural and metabolic biochemistry; Animals; Biochemistry; Biological and medical sciences; Biotechnology; Cancer; Cell growth; Cell Hypoxia; Cell Line; Cell Line, Tumor; Cell Proliferation; Cellular metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glycolysis; Glycosylation; Human; Humans; Hypoxia; Lactates; Lactic Acid - metabolism; Metabolism; Metabolism. Physicochemical requirements; Mice; Mice, Nude; Molecular and cellular biology; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; NADP - metabolism; Neoplasms - metabolism; Neoplasms - pathology; Pentose Phosphate Pathway; Phosphofructokinase-1, Liver Type - antagonists & inhibitors; Phosphofructokinase-1, Liver Type - chemistry; Phosphofructokinase-1, Liver Type - metabolism; Physiological regulation; Plant physiology and development; Protein metabolism; Proteins; Residues; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1222278

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.