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

Segatto, Marco and Fittipaldi, Raffaella and Pin, Fabrizio and Sartori, Roberta and Ko, Kyung Dae and Zare, Hossein and Fenizia, Claudio and Zanchettin, Gianpietro and Pierobon, Elisa Sefora and Hatakeyama, Shinji and Sperti, Cosimo and Merigliano, Stefano and Sandri, Marco and Filippakopoulos, Panagis and Costelli, Paola and Sartorelli, Vittorio and Caretti, Giuseppina (2017) Epigenetic Targeting of Bromodomain Protein BRD4 Counteracts Cancer Cachexia and Prolongs Survival. Nature Communications.

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, 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 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.

Item Type: Article
Date Deposited: 24 Oct 2017 00:45
Last Modified: 24 Oct 2017 00:45
URI: https://oak.novartis.com/id/eprint/28984

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