1-s2.0-S109727651730312X-main.pdf (5.68 MB)
Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function
journal contributionposted on 2020-10-15, 14:08 authored by Jun-ichi Sakamaki, Simon Wilkinson, Marcel Hahn, Nilgun Tasdemir, Jim O'Prey, William Clark, Ann Hedley, Colin Nixon, Jaclyn S Long, Maria New, Tim Van Acker, Sharon A Tooze, Scott W Lowe, Ivan Dikic, Kevin M Ryan
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.
AMPKBRD4BRD4-NUTG9a/EHMT2/KMT1CSIRT1autophagyhMOF/KAT8lysosomesselective autophagytranscriptional regulation of autophagyAMP-Activated Protein KinasesAnimalsAutophagyCarcinoma, Pancreatic DuctalCell Cycle ProteinsCell Line, TumorCell ProliferationChromatinDown-RegulationDrosophila ProteinsDrosophila melanogasterEnergy MetabolismGene Expression Regulation, NeoplasticHEK293 CellsHistocompatibility AntigensHistone-Lysine N-MethyltransferaseHumansLysosomesMice, Inbred C57BLMice, TransgenicNuclear ProteinsOncogene Proteins, FusionPancreatic NeoplasmsProtein AggregatesProtein BindingProteolysisRNA InterferenceSignal TransductionSirtuin 1TOR Serine-Threonine KinasesTime FactorsTranscription FactorsTranscription, GeneticTransfectionTooze FC00118706 Biological Sciences11 Medical and Health SciencesDevelopmental Biology