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

c-Myc is an oncogene involved in many forms of cancer. Proteomic analysis of human P-493 B lymphoma cells and PC3 prostate cancer cells shows that c-Myc regulates the microRNAs miR-23a and miR-23b to increase the expression of the mitochondrial enzyme glutaminase. This leads to enhanced glutamine metabolism and contributes to the metabolic changes in Myc-driven cancers. This paper shows that c-Myc regulates the microRNAs miR-23a and miR-23b to increase the expression of the mitochondrial enzyme glutaminase. This leads to enhanced glutamine metabolism and contributes to the metabolic changes in c-Myc-driven cancers. 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.