O-GlcNAc Signaling Regulates Cancer Metabolism

Abstract

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. The dynamic post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) couples nutrient sensing to the regulation of many important signaling pathways. We recently discovered that O-GlcNAc also serves as a key regulator of cellular metabolism itself and reprograms metabolic flux toward proliferative, pro-survival pathways. Glycosylation was dynamically induced at Ser^(529) of phosphofructokinase 1 (PFK1) under hypoxic conditions in rapidly dividing cancer cells. Glycosylation inhibited PFK1 activity and redirected glycolytic flux through the pentose phosphate pathway, thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser^(529) reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. Our studies reveal a novel mechanism for the regulation of metabolic pathways and suggest a new therapeutic approach to combat cancer.

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