Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition

Atsushi Hamabe, Masamitsu Konno, Nobuhiro Tanuma, Hiroshi Shima, Kenta Tsunekuni, Koichi Kawamoto, Naohiro Nishida, Jun Koseki, Koshi Mimori, Noriko Gotoh, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii

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Abstract

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.

Original languageEnglish
Pages (from-to)15526-15531
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number43
DOIs
Publication statusPublished - Oct 28 2014

All Science Journal Classification (ASJC) codes

  • General

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    Hamabe, A., Konno, M., Tanuma, N., Shima, H., Tsunekuni, K., Kawamoto, K., Nishida, N., Koseki, J., Mimori, K., Gotoh, N., Yamamoto, H., Doki, Y., Mori, M., & Ishii, H. (2014). Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Proceedings of the National Academy of Sciences of the United States of America, 111(43), 15526-15531. https://doi.org/10.1073/pnas.1407717111