MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat

Nat Commun. 2019 Aug 9;10(1):3623. doi: 10.1038/s41467-019-11568-0.

Abstract

Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics
  • Autophagy / physiology*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Binding Sites
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Epigenesis, Genetic*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Lysosomes / metabolism*
  • Organelle Biogenesis*
  • Polytetrafluoroethylene / metabolism*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Stem Cells
  • Transcription, Genetic

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • FOXH1 protein, human
  • Forkhead Transcription Factors
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • TFE3 protein, human
  • TFEB protein, human
  • Polytetrafluoroethylene
  • HDAC2 protein, human
  • Histone Deacetylase 2
  • Histone Deacetylases