Duncan NRI Faculty and Staff Publications
Publication Date
4-1-2022
Journal
Cancer Research
DOI
10.1158/0008-5472.CAN-21-1168
PMID
35149590
PMCID
PMC9004540
PubMedCentral® Posted Date
2-11-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Amino Acids, Animals, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Homeostasis, Humans, Lysosomes, Mice, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-myc
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.
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