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Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
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Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
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Journal Article
Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
2017
Overview
Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.
Cachexia is a metabolic syndrome leading to muscle and adipose tissue loss in majority of cancer patients. Here the authors show that, in a mouse model, BET inhibitor JQ1 counteracts muscle and adipose tissue wasting tempering cachexia and prolonging survival through a mechanism unrelated to tumour growth.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ AMP-Activated Protein Kinases - metabolism
/ Animals
/ Anorexia
/ Atrophy
/ Cachexia
/ Cachexia - prevention & control
/ Cancer
/ Forkhead Box Protein O3 - metabolism
/ Humanities and Social Sciences
/ Humans
/ Male
/ Metabolic Networks and Pathways - drug effects
/ Mice
/ Muscle, Skeletal - drug effects
/ Muscle, Skeletal - metabolism
/ Muscle, Skeletal - pathology
/ Muscles
/ Muscular Atrophy - prevention & control
/ Neoplasms, Experimental - genetics
/ Neoplasms, Experimental - metabolism
/ Neoplasms, Experimental - therapy
/ Nuclear Proteins - antagonists & inhibitors
/ Nuclear Proteins - metabolism
/ Proteins
/ Science
/ Survival
/ Transcription Factors - antagonists & inhibitors
/ Transcription Factors - genetics
