O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth

Jay Prakash Singh, Kevin Qian, Jeong Sang Lee, Jinfeng Zhou, Xuemei Han, Bichen Zhang, Qunxiang Ong, Weiming Ni, Mingzuo Jiang, Hai Bin Ruan, Min Dian Li, Kaisi Zhang, Zhaobing Ding, Philip Lee, Kamini Singh, Jing Wu, Raimund I. Herzog, Susan Kaech, Hans Guido Wendel, John R. YatesWeiping Han, Robert S. Sherwin, Yongzhan Nie, Xiaoyong Yang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)560-573
Number of pages14
JournalOncogene
Volume39
Issue number3
DOIs
StatePublished - Jan 16 2020

Bibliographical note

Funding Information:
Acknowledgements We thank Dr. Jinbo Yang for providing the Flag-PKM2 plasmid and shPKM2 lentivirus. We thank Dr. Julie T. Feld-stein 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.

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.

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