1. Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy
- Author
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Mario R. Fernandez, Franz X. Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K. Schaub, Frank C. Dorsey, Min Liu, Meredith A. Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M. Koomen, Anders E. Berglund, John L. Cleveland, Fernandez, M. R., Schaub, F. X., Yang, C., Li, W., Yun, S., Schaub, S. K., Dorsey, F. C., Liu, M., Steeves, M. A., Ballabio, A., Tzankov, A., Chen, Z., Koomen, J. M., Berglund, A. E., and Cleveland, J. L.
- Subjects
Cancer Research ,Proteasome Endopeptidase Complex ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Animal ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factor ,Lysosome ,Article ,Proto-Oncogene Proteins c-myc ,Amino Acid ,Mice ,Oncology ,Homeostasi ,Autophagy ,Animals ,Homeostasis ,Humans ,Amino Acids ,Lysosomes ,Human - Abstract
MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, AA transport, and AA and nucleotide metabolism, leading to metabolic anergy, growth arrest, and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors. Significance: MYC suppresses TFEB and autophagy and controls amino acid homeostasis by upregulating amino acid transport and the proteasome, and reactivation of TFEB disables the metabolism of MYC-driven tumors.
- Published
- 2022