Editors' ChoiceCancer

Promoting Proliferation with Nuclear Pyruvate Kinase M2

Science Signaling  06 Dec 2011:
Vol. 4, Issue 202, pp. ec337
DOI: 10.1126/scisignal.4202ec337

Pyruvate kinase M2 (PKM2) is a metabolic enzyme that has been implicated in aberrant metabolism of cancer cells. Yang et al. show that PKM2 also has nuclear functions that contribute to cancer cell proliferation. Immunofluorescence analysis and cell fractionation studies showed that treatment of glioblastoma cells with epidermal growth factor (EGF) stimulated the nuclear accumulation of PKM2, and coimmunoprecipitation studies suggested that EGF promoted an interaction between PKM2 and β-catenin in the nucleus. Coimmunoprecipitation analysis, as well as in vitro experiments, showed that the interaction of PKM2 with β-catenin depended on Lys433 of PKM2 and phosphorylation of Tyr333 of β-catenin by c-Src. Loss of c-Src activity pharmacologically or in c-Src–deficient cells blocked the EGF-mediated interaction between PKM2 and β-catenin. Chromatin immunoprecipitation analysis showed that the recruitment of β-catenin to the cyclin D1 promoter (CCND1) in response to EGF required Tyr333 and that EGF promoted the release of histone deacetylase 3 and an increase in histone 3 acetylation, all of which were inhibited by depletion of PKM2. Rescue experiments with point-mutated PKM2 showed that the β-catenin interaction did not require catalytic activity, but the interaction of PKM2 with the CCND1 promoter and induction of histone acetylation required both the residue necessary for β-catenin interaction and catalytic activity of PKM2. Production of cyclin D1 promotes cell proliferation, and depletion of either β-catenin or PKM2 reduced EGF-dependent cell proliferation both in culture and in cells intracranially injected into mice, resulting in reduced tumor growth. Analysis of human glioblastoma samples and the survival of patients showed that the amount of active c-Src, Tyr333-phosphorylated β-catenin, and nuclear PKM2 correlated and that enhanced Tyr333-phosphorylated β-catenin or nuclear PKM2 was associated with reduced survival. Thus, in addition to its cytosolic role in cancer cell metabolism, PKM2 functions as a nuclear transcriptional regulator promoting cell proliferation.

W. Yang, Y. Xia, H. Ji, Y. Zheng, J. Liang, W. Huang, X. Gao, K. Aldape, Z. Lu, Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480, 118–122 (2011). [PubMed]