Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13732-13737. doi: 10.1073/pnas.1704145115. Epub 2017 Dec 11.

O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect.

Author information

1
Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin, 130024, People's Republic of China.
2
Department of Biology, Saint Louis University, St. Louis, MO 63103.
3
Program of Bioinformatics and Computational Biology, Saint Louis University, St. Louis, MO 63103.
4
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894.
5
Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin, 130024, People's Republic of China; weim750@nenu.edu.cn.

Abstract

The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells. We show that PKM2 O-GlcNAcylation is up-regulated in various types of human tumor cells and patient tumor tissues. The modification destabilized the active tetrameric PKM2, reduced PK activity, and led to nuclear translocation of PKM2. We also observed that the modification was associated with an increased glucose consumption and lactate production and enhanced level of lipid and DNA synthesis, indicating that O-GlcNAcylation promotes the Warburg effect. In vivo experiments showed that blocking PKM2 O-GlcNAcylation attenuated tumor growth. Thus, we demonstrate that O-GlcNAcylation is a regulatory mechanism for PKM2 in cancer cells and serves as a bridge between PKM2 and metabolic reprogramming typical of the Warburg effect.

KEYWORDS:

O-GlcNAcylation; PKM2; Warburg effect; cancer metabolism

PMID:
29229835
PMCID:
PMC5748163
DOI:
10.1073/pnas.1704145115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center