Epigenetic Targeting of Bromodomain Protein BRD4 Counteracts Cancer Cachexia and Prolongs Survival

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for approximately one third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated.We have found that (+)-JQ1 administration protects tumor-bearing mice from body weight loss, muscle and adipose tissue wasting. Remarkably, in C26-tumor bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq analyses, we unveil that the BET proteins directly promote the muscle atrophy program during cachexia. Consistently, BET pharmacological blockade prevents the activation of catabolic genes associated with skeletal muscle atrophy and decreases IL6 systemic levels. Overall, these findings indicate that BET may represent a promising therapeutic target in the management of cancer cachexia. Overall design: To examine BRD4 genome-wide distribution in skeletal muscle during cachexia, we compared BRD4 occupancy in control skeletal muscle, in muscles from C26-tumor bearing mice treated with JQ1 and in muscles from C26-tumor bearing mice treated with JQ1 inactive enantiomer. Tumor-bearing mice were inoculated with C26 tumor cells by dorsal s.c. injection. The day after tumor cells inoculation animals were treated either with JQ1 or the inactive enantiomer.