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

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

Author information

1
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt, Germany.
3
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Molecular Cell Biology of Autophagy, Francis Crick Institute, London NW1 1AT, UK.
5
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA.
6
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt, Germany; Institute of Immunology, School of Medicine, University of Split, 21 000 Split, Croatia.
7
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Electronic address: k.ryan@beatson.gla.ac.uk.

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

PMID:
28525743
PMCID:
PMC5446411
DOI:
10.1016/j.molcel.2017.04.027
[Indexed for MEDLINE]
Free PMC Article

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