Cancer cells are known to adopt aerobic glycolysis in order to fuel tumor growth, but the molecular basis of this metabolic shift remains largely undefined. O-GlcNAcase (OGA) is an enzyme harboring O-linked β-N-acetylglucosamine (O-GlcNAc) hydrolase and cryptic lysine acetyltransferase activities. Here, we report that OGA is upregulated in a wide range of human cancers and drives aerobic glycolysis and tumor growth by inhibiting pyruvate kinase M2 (PKM2). PKM2 is dynamically O-GlcNAcylated in response to changes in glucose availability. Under high glucose conditions, PKM2 is a target of OGA-associated acetyltransferase activity, which facilitates O-GlcNAcylation of PKM2 by O-GlcNAc transferase (OGT). O-GlcNAcylation inhibits PKM2 catalytic activity and thereby promotes aerobic glycolysis and tumor growth. These studies define a causative role for OGA in tumor progression and reveal PKM2 O-GlcNAcylation as a metabolic rheostat that mediates exquisite control of aerobic glycolysis.
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We thank Dr. Jinbo Yang for providing the Flag-PKM2 plasmid and shPKM2 lentivirus. We thank Dr. Julie T. Feldstein for helping with immunohistochemical analysis of human cancer tissues. We thank Dr. Neeraj Tiwari for helping with sucrose density gradient ultracentrifugation. This work was supported by NIH R01 DK089098, P01 DK057751, Yale Comprehensive Cancer Center Pilot Grant, and American Cancer Society Research Scholar Grant to XY.
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Singh, J.P., Qian, K., Lee, JS. et al. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 39, 560–573 (2020). https://doi.org/10.1038/s41388-019-0975-3
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