O‐GlcNAc Signaling Regulates Cancer Metabolism

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 Ser529 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.