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Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Author(s)
Clish, Clary B.; Bronson, Roderick T.; Dayton, Talya L.; Gocheva, Vasilena; Miller, Kathryn; Israelsen, William James; Bhutkar, Arjun; Davidson, Shawn Michael; Luengo, Alba; Jacks, Tyler E.; Vander Heiden, Matthew G.; ... Show more Show less
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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[superscript −/−]). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2[superscript −/−] 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.
Date issued
2016-05
URI
http://hdl.handle.net/1721.1/108777
Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Dayton, Talya L. et al. “Germline Loss of PKM2 Promotes Metabolic Distress and Hepatocellular Carcinoma.” Genes & Development 30.9 (2016): 1020–1033.
Version: Final published version
ISSN
0890-9369
1549-5477

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