RRC ID 66091
Author Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O'Prey J, Clark W, Hedley A, Nixon C, Long JS, New M, Van Acker T, Tooze SA, Lowe SW, Dikic I, Ryan KM.
Title Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function.
Journal Mol Cell
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.
Volume 66(4)
Pages 517-532.e9
Published 2017-5-18
DOI 10.1016/j.molcel.2017.04.027
PII S1097-2765(17)30312-X
PMID 28525743
PMC PMC5446411
MeSH 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
IF 15.584
Human and Animal Cells KP4(RCB1005) PK-1(RCB1972)