Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1

Abstract

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.

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

“…This reason may be that different dosages and treating time of have different effects on the proliferation of some cell lines, PKM2 is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth (Wong et al, 2013). Recent studies indicated that nuclear PKM2 could activate gene transcription and cell proliferation in human glioblastoma, prostate cancer and breast cancer cells (Gao et al, 2012;Lee et al, 2008;Luo et al, 2011a;Luo et al, 2011b). Here we observed its role in EGFinduced EMT and cell motility in HCC cells.…”

“…Therefore, β-catenin, HIF-1α and PKM2 could be key molecules involved in the EMT process in HCC. Interestingly, there have been many reports demonstrating the interactions between these molecules, which were important for tumor proliferation, invasion and progression (Luo et al, 2011a;Yang et al, 2011;Zhang et al, 2013). It could be postulated that the EMT process induced by different factors in HCC could be attributed to some common mechanisms involving β-catenin, HIF-1α and PKM2 simultaneously.…”

miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect

“…Knockdown of PKM2 compromised miRNA-induced growth inhibition. For cancer cells, PKM2 not only supports cell growth via Warburg effect as a metabolic enzyme, but also promotes transactivation of HIF-1 target genes as a transcription coactivator (31). It implied that other mechanisms were probably also involved.…”

Metabolic reprogramming of the tumor

“…Unlike PKM1, the less active PKM2 can be inhibited by phosphotyrosine-containing proteins, allowing accumulation of phosphorylated glycolytic intermediates, which will be used for biosynthesis (Christofk et al, 2008). Curiously, it was found that PKM transcription is activated by HIF-1 and PKM2, but not PKM1, becomes associated with HIF-1a, enhancing HIF-1 binding to its target genes (Luo et al, 2011), thus constituting a positive feedback loop. The lower activity of PKM2 contributes to the lower use of pyruvate by mitochondria and thus to supplement the effect of the AKT oncogene (Elstrom et al, 2004).…”