Journal Article

O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth

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

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Acetyltransferase / Glycolysis / Hydrolase / Kinases / Lysine / Metabolism / N-Acetylglucosamine / O-GlcNAcylation / Pyruvate kinase / Pyruvic acid