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.

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Pin, Fabrizio;Costelli, Paola;
2017-01-01

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.
2017
8
1
1707
1-16
http://www.nature.com/ncomms/index.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700099/
Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all)
Segatto, Marco; Fittipaldi, Raffaella; Pin, Fabrizio; Sartori, Roberta; Dae Ko, Kyung; Zare, Hossein; Fenizia, Claudio; Zanchettin, Gianpietro; Pierobon, Elisa Sefora; Hatakeyama, Shinji; Sperti, Cosimo; Merigliano, Stefano; Sandri, Marco; Filippakopoulos, Panagis; Costelli, Paola; Sartorelli, Vittorio; Caretti, Giuseppina
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1655251
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