Format

Send to

Choose Destination
Nat Cell Biol. 2017 Nov;19(11):1358-1370. doi: 10.1038/ncb3630. Epub 2017 Oct 23.

PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis.

Liu F1, Ma F2, Wang Y3, Hao L2, Zeng H1, Jia C2, Wang Y1, Liu P4,5, Ong IM4,5, Li B2, Chen G3, Jiang J2, Gong S3,6, Li L2,7,8, Xu W1.

Author information

1
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
2
School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
3
Department of Materials Science and Engineering and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, Wisconsin 53715, USA.
4
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
5
UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
6
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
7
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
8
School of Life Sciences, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China.

Abstract

Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions.

PMID:
29058718
PMCID:
PMC5683091
DOI:
10.1038/ncb3630
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center