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

Marco Segatto, Raffaella Fittipaldi, Fabrizio Pin, Roberta Sartori, Kyung Dae Ko, Hossein Zare, Claudio Fenizia, Gianpietro Zanchettin, Elisa Sefora Pierobon, Shinji Hatakeyama, Cosimo Sperti, Stefano Merigliano, Marco Sandri, Panagis Filippakopoulos, Paola Costelli, Vittorio Sartorelli and Giuseppina Caretti ()
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Marco Segatto: Universita’ degli Studi di Milano
Raffaella Fittipaldi: Universita’ degli Studi di Milano
Fabrizio Pin: University of Turin
Roberta Sartori: University of Padova
Kyung Dae Ko: Laboratory of Muscle Stem Cells and Gene Regulation, NIH/NIAMS
Hossein Zare: Laboratory of Muscle Stem Cells and Gene Regulation, NIH/NIAMS
Claudio Fenizia: Universita’ degli Studi di Milano
Gianpietro Zanchettin: University of Padua
Elisa Sefora Pierobon: University of Padua
Shinji Hatakeyama: Novartis Pharma AG
Cosimo Sperti: University of Padua
Stefano Merigliano: University of Padua
Marco Sandri: Venetian Institute of Molecular Medicine
Panagis Filippakopoulos: University of Oxford
Paola Costelli: University of Turin
Vittorio Sartorelli: Laboratory of Muscle Stem Cells and Gene Regulation, NIH/NIAMS
Giuseppina Caretti: Universita’ degli Studi di Milano

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01645-7

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