Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 7 June 2011
Vol. 4, Issue 176, p. ec157
[DOI: 10.1126/scisignal.4176ec157]


Cancer Biology Shifting the Metabolic Program

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Many cancer cells have altered metabolism, showing decreased O2 consumption as compared with noncancerous cells and producing lactate even in the presence of abundant oxygen. This aberrant metabolism is associated with expression of the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) (see Tennant). Luo et al. add an intriguing twist to the story by showing that—independent of its biochemical activity—PKM2 promotes aerobic glycolysis through interactions with hypoxia-inducible factor 1 (HIF-1), a transcription factor induced under hypoxic conditions that stimulates the transcription of genes implicated in various aspects of cancer biology, including the switch from oxidative to glycolytic metabolism. After determining that abundance of the mRNA encoding PKM2 was increased by hypoxia, and that this depended on HIF-1α, the authors identified PKM2 as a HIF-1 target: They identified a candidate hypoxia response element (HRE)–binding site in PKM2 and showed association of HIF-1α to this region by chromatin immunoprecipitation analysis and the HIF-1α–dependent activation of a reporter gene containing the PKM2 HRE. Immunoblot analysis revealed PKM2 in the nucleus, and a proteomic screen indicated that it bound to HIF-1α, an interaction confirmed by coimmunoprecipitation analysis and in vitro pull-down assays. Transfection of a tagged form of PKM2 enhanced transcription of a HIF-1 reporter, whereas PKM2 knockdown decreased it. PKM2 did not affect HIF-1 abundance; rather, it enhanced HIF-1α binding to the HREs of target genes, recruitment of the transcriptional coactivator p300, and target gene transactivation. Mutational analysis indicated that PKM2’s catalytic activity was not required for its stimulation of HIF-1α transactivation. Noting that PKM2 contains a prolyl hydroxylation motif, the authors combined mass spectrometric analysis with immunoblot analysis to confirm its prolyl hydroxylation. Prolyl hydroxylase 3 (PHD3)–dependent hydroxylation enhanced PKM2-mediated HIF-1α transactivation; indeed, PKM2 and PHD3 colocalized with HIF-1α at the HREs of target genes. Knockdown of PKM2 or PHD3 decreased the expression of HIF-1 target genes; moreover, PHD3 knockdown increased O2 consumption in renal cancer cells and decreased their glucose and lactate content. Thus, the authors propose that PKM2 participates in a positive feedback loop with HIF-1 to promote the shift to glycolytic metabolism.

W. Luo, H. Hu, R. Chang, J. Zhong, M. Knabel, R. O'Meally, R. N. Cole, A. Pandey, G. L. Semenza, Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011). [PubMed]

D. A. Tennant, PK-M2 makes cells sweeter on HIF1. Cell 145, 647–649 (2011). [PubMed]

Citation: E. M. Adler, Shifting the Metabolic Program. Sci. Signal. 4, ec157 (2011).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882