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c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism

Abstract

Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen1,2. Notwithstanding the renewed interest in the Warburg effect, cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate3. Glutamine, which is highly transported into proliferating cells4,5, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells, but the regulation of glutamine metabolism is not well understood1,6. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs7,8 and stimulate cell proliferation9, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells. This leads to upregulation of glutamine catabolism10. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis11. The unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of miRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.

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Figure 1: Myc enhances the expression of mitochondrial protein glutaminase.
Figure 2: Glutamine and glutaminase are necessary for Myc-mediated cancer cell proliferation and survival.
Figure 3: Myc increases GLS protein by transcriptionally repressing miR-23a/b that target the GLS 3′ UTR.

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Acknowledgements

The authors want to thank L. Blosser and A. Tam for their help in flow cytometry analysis, and H. Y. Zhang for her help with statistical analysis. This work was partially supported by NIH Awards NHLBI NO1-HV-28180, NCI R01CA051497, NCI R01CA57341, NCI R01CA120185, NCI P50CA58236, Rita Allen Foundation, Leukemia and Lymphoma Society, and Sol Goldman Center for Pancreatic Cancer Research.

Author Contributions P.G., K.K., T.O., A.M.D., J.E.V., J.T.M. and C.V.D. designed experiments. P.G., I.T., T.-C.C., Y.-S.L. and K.I.Z. performed experiments. K.K. and T.O. provided reagents. P.G. and C.V.D. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Ping Gao or Chi V. Dang.

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Gao, P., Tchernyshyov, I., Chang, TC. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009). https://doi.org/10.1038/nature07823

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