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Science 337 (6097): 975-980

Copyright © 2012 by the American Association for the Advancement of Science

Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Wen Yi,1,2 Peter M. Clark,1,2 Daniel E. Mason,3 Marie C. Keenan,4 Collin Hill,4 William A. Goddard, III,5 Eric C. Peters,3 Edward M. Driggers,4 Linda C. Hsieh-Wilson1,2,*

Abstract: 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.

1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
2 Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
3 Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
4 Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
5 Materials and Process Simulation Center, California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA.

* To whom correspondence should be addressed. E-mail: lhw{at}caltech.edu


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