Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis

Nat Cell Biol. 2017 May;19(5):445-456. doi: 10.1038/ncb3517. Epub 2017 Apr 24.

Abstract

A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis. In addition, we found that miR-200c-5p specifically targets SIRT2, downregulating its expression. Furthermore, SIRT2 overexpression in hPSCs significantly affected energy metabolism, altering stem cell functions such as pluripotent differentiation properties. Taken together, our results identify the miR-200c-SIRT2 axis as a key regulator of metabolic reprogramming (Warburg-like effect), via regulation of glycolytic enzymes, during human induced pluripotency and pluripotent stem cell function.

Publication types

  • Meta-Analysis

MeSH terms

  • Acetylation
  • Cell Differentiation*
  • Cell Lineage
  • Cell Survival
  • Cellular Reprogramming
  • Computational Biology
  • Databases, Genetic
  • Energy Metabolism*
  • Gene Expression Regulation, Enzymologic
  • Glycolysis
  • HEK293 Cells
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oxidative Phosphorylation
  • Phenotype
  • Pluripotent Stem Cells / enzymology*
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Sirtuin 2 / genetics
  • Sirtuin 2 / metabolism*
  • Time Factors
  • Transfection

Substances

  • MIRN200 microRNA, human
  • MicroRNAs
  • SIRT1 protein, human
  • SIRT2 protein, human
  • Sirtuin 1
  • Sirtuin 2