PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis

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

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.

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism*
  • Calcium / metabolism
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Endoplasmic Reticulum / metabolism
  • Female
  • Glycolysis / physiology*
  • Guanylate Cyclase / metabolism*
  • HEK293 Cells
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • MCF-7 Cells
  • Membrane Proteins / metabolism*
  • Methylation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / metabolism
  • Neoplasm Metastasis / pathology
  • Oxidative Phosphorylation
  • Thyroid Hormones / metabolism*

Substances

  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Inositol 1,4,5-Trisphosphate Receptors
  • Membrane Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • CARD11 protein, human
  • Guanylate Cyclase
  • Calcium