Background and aims: Skeletal muscle loss is a hallmark of cancer cachexia. This multifactorial syndrome is responsible for about 25% of cancer deaths. In particular, muscle wasting in cachectic patients often leads to increased morbidity and mortality, decreased beneficial effects from chemotherapy, and poorer quality of life. Therefore, the development of therapeutic strategies aimed at preventing muscle loss during cancer cachexia is attracting increasing clinical interest. To date, no effective therapies for preventing cancer cachexia are available. Recently, we showed that the bromodomain protein BRD4 regulates pro-atrophic genes and that the administration of the small BET inhibitor JQ1 increases muscle fiber size, protecting from dexamethasone-induced atrophy in C2C12 myotubes. In the present study, we evaluated the effect of BRD4 inhibition by JQ1 treatment in skeletal muscle of cachectic mice. Methods: C26-tumor bearing mice were treated with JQ1 or vehicle, daily. After 12 days, body weight, skeletal muscle weight, and the anabolic/catabolic pathways involved in skeletal muscle homeostasis were evaluated. Epigenetic and transcriptional regulation of key genes involved in cancer cachexia was also analyzed by ChIP, ChIP-seq, and RT-PCR. Results: JQ1 treatment prolongs survival by protecting tumor-bearing mice from body weight loss, adipose tissue atrophy, and muscle wasting. In skeletal muscle, pharmacological treatment prevents muscle loss through two different mechanisms, both converging on the transcriptional regulation of muscle atrophy-related genes: the former involves JQ1-mediated displacement of BRD4 from atrogenes; the latter is ascribable to the suppression of IL6/AMPK/FoxO3 axis. Conclusions: The obtained results suggest that the epigenetic modulation mediated by BET inhibitors is able to efficiently prevent muscle wasting and increase lifespan of tumorbearing mice, thus representing a promising therapeutic approach for the management of cancer cachexia.
The BET inhibitor JQ1 counteracts skeletal muscle loss during cancer cachexia and prolong survival
M. Segatto;
2016-01-01
Abstract
Background and aims: Skeletal muscle loss is a hallmark of cancer cachexia. This multifactorial syndrome is responsible for about 25% of cancer deaths. In particular, muscle wasting in cachectic patients often leads to increased morbidity and mortality, decreased beneficial effects from chemotherapy, and poorer quality of life. Therefore, the development of therapeutic strategies aimed at preventing muscle loss during cancer cachexia is attracting increasing clinical interest. To date, no effective therapies for preventing cancer cachexia are available. Recently, we showed that the bromodomain protein BRD4 regulates pro-atrophic genes and that the administration of the small BET inhibitor JQ1 increases muscle fiber size, protecting from dexamethasone-induced atrophy in C2C12 myotubes. In the present study, we evaluated the effect of BRD4 inhibition by JQ1 treatment in skeletal muscle of cachectic mice. Methods: C26-tumor bearing mice were treated with JQ1 or vehicle, daily. After 12 days, body weight, skeletal muscle weight, and the anabolic/catabolic pathways involved in skeletal muscle homeostasis were evaluated. Epigenetic and transcriptional regulation of key genes involved in cancer cachexia was also analyzed by ChIP, ChIP-seq, and RT-PCR. Results: JQ1 treatment prolongs survival by protecting tumor-bearing mice from body weight loss, adipose tissue atrophy, and muscle wasting. In skeletal muscle, pharmacological treatment prevents muscle loss through two different mechanisms, both converging on the transcriptional regulation of muscle atrophy-related genes: the former involves JQ1-mediated displacement of BRD4 from atrogenes; the latter is ascribable to the suppression of IL6/AMPK/FoxO3 axis. Conclusions: The obtained results suggest that the epigenetic modulation mediated by BET inhibitors is able to efficiently prevent muscle wasting and increase lifespan of tumorbearing mice, thus representing a promising therapeutic approach for the management of cancer cachexia.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
