Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Genes Dev. 2016 May 1;30(9):1020-33. doi: 10.1101/gad.278549.116. Epub 2016 Apr 28.

Abstract

Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2(-/-)). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2(-/-) mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

Keywords: HCC; PKM2; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / physiopathology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cell Proliferation / genetics
  • Diet, High-Fat
  • Embryo, Mammalian
  • Embryonic Development / genetics
  • Energy Metabolism / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Germ-Line Mutation
  • Growth and Development / genetics
  • Hepatocytes / cytology
  • Homeostasis / genetics
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / physiopathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mice
  • Protein Isoforms
  • Thyroid Hormones / genetics*
  • Thyroid Hormones / metabolism*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Protein Isoforms
  • Thyroid Hormones
  • thyroid hormone-binding proteins