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Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy

Mario R Fernandez1, Franz X Schaub1, Chunying Yang1

  • 1Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, Florida.

Cancer Research
|February 12, 2022
PubMed

Insights

MYC oncoproteins suppress autophagy by inhibiting transcription factor EB (TFEB). Reactivating TFEB disrupts MYC-driven cancer metabolism, offering therapeutic strategies for Burkitt lymphoma.

Area of Science:

  • Cancer Biology
  • Cellular Metabolism
  • Molecular Oncology

Background:

  • MYC oncoproteins drive metabolic reprogramming essential for cancer cell growth.
  • Autophagy is crucial for amino acid homeostasis in normal cells under nutrient stress.

Purpose of the Study:

  • To investigate the role of MYC in regulating autophagy and amino acid metabolism in B cells.
  • To explore the therapeutic potential of targeting the autophagy-lysosomal pathway in MYC-driven malignancies.

Main Methods:

  • Analysis of autophagy suppression by MYC in normal, premalignant, and malignant B cells (Eμ-Myc mice and human Burkitt lymphoma).
  • Investigated MYC's antagonism of transcription factor EB (TFEB), a master autophagy regulator.
  • Examined mechanisms sustaining amino acid pools, including proteasome induction and amino acid transport.

Main Results:

  • MYC suppresses autophagy by inhibiting TFEB expression and function in various B cell contexts.
  • MYC-driven B cells sustain amino acid pools via proteasome induction and enhanced amino acid transport.
  • Reactivation of TFEB and the autophagy-lysosomal pathway disrupts cancer cell metabolism, leading to growth arrest and apoptosis.

Conclusions:

  • MYC actively suppresses the autophagy-lysosomal pathway through TFEB inhibition to support cancer cell metabolism.
  • Targeting TFEB or the autophagy-lysosomal pathway presents a viable therapeutic strategy against MYC-driven cancers.
  • Combined approaches, such as amino acid restriction and proteasome inhibitors, may enhance therapeutic efficacy.

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