Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma
- Talya L. Dayton1,2,
- Vasilena Gocheva1,2,
- Kathryn M. Miller1,2,
- William J. Israelsen1,2,3,
- Arjun Bhutkar1,2,
- Clary B. Clish4,
- Shawn M. Davidson1,2,
- Alba Luengo1,2,
- Roderick T. Bronson5,
- Tyler Jacks1,6 and
- Matthew G. Vander Heiden1,7
- 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 4Metabolite Profiling Platform, Broad Institute, Cambridge, Massachusetts 02142, USA;
- 5Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, Massachusetts 01536, USA;
- 6Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 7Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
- Corresponding authors: tjacks{at}mit.edu, mvh{at}mit.edu
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.278549.116.
- Received January 26, 2016.
- Accepted March 23, 2016.
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