Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma.

Genes Dev
Authors
Keywords
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.

Year of Publication
2016
Journal
Genes Dev
Volume
30
Issue
9
Pages
1020-33
Date Published
2016 05 01
ISSN
1549-5477
URL
DOI
10.1101/gad.278549.116
PubMed ID
27125672
PubMed Central ID
PMC4863734
Links
Grant list
P01 CA117969 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 CA168653 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States