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

Ping Gao, Irina Tchernyshyov, Tsung Cheng Chang, Yun Sil Lee, Kayoko Kita, Takafumi Ochi, Karen I. Zeller, Angelo M. De Marzo, Jennifer E. Van Eyk, Joshua T. Mendell, Chi V. Dang

Research output: Contribution to journalArticle

1228 Scopus citations

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 oxygen. 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 lactate. Glutamine, which is highly transported into proliferating cells, 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 understood. Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, 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 catabolism. 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 synthesis. 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.

Original languageEnglish (US)
Pages (from-to)762-765
Number of pages4
JournalNature
Volume458
Issue number7239
DOIs
StatePublished - Apr 9 2009

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    Gao, P., Tchernyshyov, I., Chang, T. C., Lee, Y. S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., & Dang, C. V. (2009). C-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 458(7239), 762-765. https://doi.org/10.1038/nature07823