A positive feedback loop between Myc and aerobic glycolysis sustains tumor growth in a Drosophila tumor model

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Abstract

Cancer cells usually exhibit aberrant cell signaling and metabolic reprogramming. However, mechanisms of crosstalk between these processes remain elusive. Here we show that in an in vivo tumor model expressing oncogenic Drosophila Homeodomain-interacting protein kinase (Hipk), tumor cells display elevated aerobic glycolysis. Mechanistically, elevated Hipk drives transcriptional upregulation of Drosophila Myc (dMyc; MYC in vertebrates) likely through convergence of multiple perturbed signaling cascades. dMyc induces robust expression of pfk2 (encoding 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFKFB in vertebrates) among other glycolytic genes. Pfk2 catalyzes the synthesis of fructose-2,6-bisphosphate, which acts as a potent allosteric activator of Phosphofructokinase (Pfk) and thus stimulates glycolysis. Pfk2 and Pfk in turn are required to sustain dMyc protein accumulation post-transcriptionally, establishing a positive feedback loop. Disruption of the loop abrogates tumorous growth. Together, our study demonstrates a reciprocal stimulation of Myc and aerobic glycolysis and identifies the Pfk2-Pfk governed committed step of glycolysis as a metabolic vulnerability during tumorigenesis.

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Data generated or analyzed during this study are available in the manuscript and supporting files.

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Kenneth Kin Lam Wong

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada

Competing interests
The authors declare that no competing interests exist.
Jenny Zhe Liao

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada

Competing interests
The authors declare that no competing interests exist.
Esther M Verheyen

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada

For correspondence
everheye@sfu.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9795-5094

Funding

Canadian Institutes of Health Research (PJT-156204)

Esther M Verheyen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.