BRD4 blockade prevents skeletal muscle loss during cancer cachexia

Skeletal muscle wasting is a hallmark of cancer cachexia, which leads to increased morbidity and mortality, decreased beneficial effects from chemotherapeutic treatment, and poorer quality of life. Therefore, the development of therapeutic avenues addressed at preventing muscle wasting during cancer cachexia is attracting increasing clinical interest. To date, no effective therapies for cachexia are available. Recently, we described that the bromodomain protein BRD4 regulates pro‐atrophic genes and that treatment with the small bromodomain inhibitor JQ1 enhances muscle fiber size, protecting from dexamethasone‐induced muscle atrophy in C2C12 myotubes. In the present study, we evaluated the involvement of BRD4 in skeletal muscle wasting of cachectic mice. To this aim, C26‐tumor bearing mice were chronically treated with the BET inhibitor JQ1 or vehicle. Body weight, skeletal muscle weight and the anabolic/catabolic pathways involved in skeletal muscle homeostasis were analyzed. Our results show that JQ1 treatment blocks muscle‐specific ubiquitin ligases expression and protects tumor‐bearing mice from body weight loss and muscle wasting. Furthermore, JQ1 administration prevents adipose tissue loss and significantly prolongs survival. We show that the BET protein BRD4 promotes cachexia through activation of the muscle atrophy program and through an IL6‐dependent signaling pathway that modulates atrogenes transcription. Consistently, BET proteins pharmacological blockade reduces IL6 systemic levels and prevents the activation of skeletal muscle catabolic genes. Overall, our data uncover that BET proteins may represent a promising therapeutic target to counteract cancer cachexia.