Abstract
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.
Highlights
Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting
Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and muscle and adipose tissue wasting, which lead to weight loss despite adequate nutritional support[1]
To explore the involvement of the bromodomain and extra-terminal domain (BET) inhibitor (+)-JQ1 in the activation of catabolic genes and muscle wasting in cancer cachexia, we first established (+)-JQ1 sensitivity in nine cell lines commonly employed in experimental models of cancer cachexia, by assessment of (+)-JQ1 impact on viability after 72 h of (+)-JQ1 treatment, at three different doses (0.1, 0.5, and 1 μM)
Summary
Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting It is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and muscle and adipose tissue wasting, which lead to weight loss despite adequate nutritional support[1]. It accompanies majority of cancer patients with advanced disease, and has a stronger prevalence at earlier cancer stages in solid tumors, such as gastric, pancreatic, lung, colorectal, and head and neck[2]. Coactivators and chromatin regulators likely take part in the transcriptional modulation of catabolic genes, the epigenetic mechanisms underlying their activation in cachexia are poorly elucidated
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