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

Weibo Luo1, Hongxia Hu, Ryan Chang

  • 1Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Cell
|May 31, 2011
PubMed

Insights

Pyruvate kinase M2 (PKM2) protein interacts with hypoxia-inducible factor 1 (HIF-1) to enhance cancer cell gene activity and alter glucose metabolism. This interaction promotes tumor growth and creates a feedback loop for sustained cancer cell function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Pyruvate kinase M2 (PKM2) is an alternatively spliced product of the PKM2 gene, distinct from PKM1.
  • PKM2 influences cancer cell glucose metabolism and tumorigenesis through mechanisms beyond its known enzymatic activity.

Purpose of the Study:

  • To investigate the role of PKM2 in regulating glucose metabolism and tumorigenesis.
  • To elucidate the molecular mechanisms by which PKM2 affects hypoxia-inducible factor 1 (HIF-1) activity.

Main Methods:

  • Investigated PKM2 gene transcription activation by HIF-1.
  • Analyzed PKM2 interaction with HIF-1α and its effect on HIF-1 target gene transactivation.
  • Examined the role of prolyl hydroxylase 3 (PHD3) in PKM2 function using mass spectrometry and antibody assays.
  • Assessed the impact of PHD3 knockdown on cellular metabolism.

Main Results:

  • PKM2, not PKM1, interacts with HIF-1α, enhancing HIF-1 binding and p300 recruitment to promote transactivation of HIF-1 target genes.
  • Prolyl hydroxylase 3 (PHD3) enhances PKM2's interaction with HIF-1α and its coactivator function.
  • PKM2 is hydroxylated on proline-403/408, and PHD3 knockdown impairs PKM2 coactivator function, reduces glucose uptake and lactate production, and increases oxygen consumption.
  • PKM2 forms a positive feedback loop with HIF-1, reprogramming glucose metabolism in cancer cells.

Conclusions:

  • PKM2 plays a critical role in regulating cancer cell metabolism and promoting tumorigenesis through its interaction with HIF-1.
  • The PKM2-HIF-1 interaction represents a novel mechanism for metabolic reprogramming in cancer.
  • Targeting the PKM2-HIF-1 pathway may offer therapeutic strategies for cancer treatment.

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