Pyruvate Kinase M2 is a PHD3-stimulated Coactivator for Hypoxia-Inducible Factor 1

By W. Luo, Hongxia Hu, R. Chang, Jun Zhong, Matthew K. Knabel, Robert N. O’Meally, R. Cole, Akhilesh Pandey, G. Semenza. Cell, 2011

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SUMMARY 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.

Subfields: Cancer Research, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/39b72b44b0c77c3fce07400c5ab564793b448f71

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Citations in the corpus

Hypoxia-Inducible Factors in Physiology and Medicine (2012, background): “…transition (Mak et al., 2010), genetic instability (Huang et al., 2007), vascularization (Liao and Johnson, 2007), glucose metab- olism (Luo et al., 2011), pH regulation (Swietach et al., 2007), immune evasion (Lukashev et al., 2007), invasion andmetastasis (Chan andGiaccia, 2007),…”
Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, positive): “The PKM2 dimer can translocate to the nucleus where it will interact with Hif-1α and regulate expression of numerous pro-glycolytic enzymes (Luo et al., 2011), an event that is dependent on ERK1/2 activity and regulated by Jumoji C domaincontaining dioxygenase (JMJD5) (Wang et al., 2014; Yang et…”
Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “Luo et al. (2011) found that the M2 isoform (PKM2) is itself a HIF target gene and that it is able to interact with both HIF1A and HIF2A, via the M2-specific exon 10 region.”
Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review). (2012, background): “Notably, new data also show that PKM2 may be a strong partner for HIF1 transcription activity in hypoxia, and since PKM2 gene transcription is also activated by HIF1, this suggests that PKM2 participates in a positive feedback loop of HIF1 transcription in cancer cells (65).”
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “Cells Is to Facilitate Anabolic Metabolism Accompanying the resurgence of interest in the metabolic effects of PKM2 have been recent reports on ‘‘non-metabolic’’ functions of PKM2 (Luo et al., 2011; Yang et al., 2011).”
Signal transduction in cancer. (2015, neutral): “PKM2 can also enter the nucleus and play a role in gene expression (Luo et al. 2011; Gao et al. 2012).”