Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function

Mol Cell. 2017 May 18;66(4):517-532.e9. doi: 10.1016/j.molcel.2017.04.027.

Abstract

Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.

Keywords: AMPK; BRD4; BRD4-NUT; G9a/EHMT2/KMT1C; SIRT1; autophagy; hMOF/KAT8; lysosomes; selective autophagy; transcriptional regulation of autophagy.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Autophagy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin / genetics
  • Chromatin / metabolism
  • Down-Regulation
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Energy Metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Protein Aggregates
  • Protein Binding
  • Proteolysis
  • RNA Interference
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transfection

Substances

  • BRD4 protein, human
  • BRD4-NUT fusion oncogene protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • Chromatin
  • Drosophila Proteins
  • Histocompatibility Antigens
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Protein Aggregates
  • Transcription Factors
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • SIRT1 protein, human
  • Sirtuin 1