Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1

Weibo Luo, Hongxia Hu, Ryan Chang, Jun Zhong, Matthew Knabel, Robert O'Meally, Robert N. Cole, Akhilesh Pandey, Gregg L. Semenza

Research output: Contribution to journalArticle

640 Citations (Scopus)

Abstract

The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O2 consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells.

Original languageEnglish (US)
Pages (from-to)732-744
Number of pages13
JournalCell
Volume145
Issue number5
DOIs
StatePublished - May 27 2011
Externally publishedYes

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Hypoxia-Inducible Factor 1
Pyruvate Kinase
Genes
Cells
Metabolism
Glucose
Transcriptional Activation
Neoplasms
Hydroxylation
Hydroxyproline
Response Elements
Transcription
2-oxoglutarate 3-dioxygenase proline
Proline
Mass spectrometry
Anti-Idiotypic Antibodies
Lactic Acid
Assays
Mass Spectrometry
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., ... Semenza, G. L. (2011). Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell, 145(5), 732-744. https://doi.org/10.1016/j.cell.2011.03.054

Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. / Luo, Weibo; Hu, Hongxia; Chang, Ryan; Zhong, Jun; Knabel, Matthew; O'Meally, Robert; Cole, Robert N.; Pandey, Akhilesh; Semenza, Gregg L.

In: Cell, Vol. 145, No. 5, 27.05.2011, p. 732-744.

Research output: Contribution to journalArticle

Luo, W, Hu, H, Chang, R, Zhong, J, Knabel, M, O'Meally, R, Cole, RN, Pandey, A & Semenza, GL 2011, 'Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1', Cell, vol. 145, no. 5, pp. 732-744. https://doi.org/10.1016/j.cell.2011.03.054
Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-744. https://doi.org/10.1016/j.cell.2011.03.054
Luo, Weibo ; Hu, Hongxia ; Chang, Ryan ; Zhong, Jun ; Knabel, Matthew ; O'Meally, Robert ; Cole, Robert N. ; Pandey, Akhilesh ; Semenza, Gregg L. / Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. In: Cell. 2011 ; Vol. 145, No. 5. pp. 732-744.
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