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

Author

Listed:
  • Marco Segatto

    (Universita’ degli Studi di Milano)

  • Raffaella Fittipaldi

    (Universita’ degli Studi di Milano)

  • Fabrizio Pin

    (University of Turin)

  • Roberta Sartori

    (University of Padova
    Venetian Institute of Molecular Medicine)

  • 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
    Laboratory of Muscle Stem Cells and Gene Regulation, NIH/NIAMS)

  • Panagis Filippakopoulos

    (University of Oxford
    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)

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.

Suggested Citation

  • Marco Segatto & Raffaella Fittipaldi & Fabrizio Pin & Roberta Sartori & Kyung Dae Ko & Hossein Zare & Claudio Fenizia & Gianpietro Zanchettin & Elisa Sefora Pierobon & Shinji Hatakeyama & Cosimo Spert, 2017. "Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01645-7
    DOI: 10.1038/s41467-017-01645-7
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    Cited by:

    1. Yoshihiro Hayashi & Yasushige Kamimura-Aoyagi & Sayuri Nishikawa & Rena Noka & Rika Iwata & Asami Iwabuchi & Yushin Watanabe & Natsumi Matsunuma & Kanako Yuki & Hiroki Kobayashi & Yuka Harada & Hirono, 2024. "IL36G-producing neutrophil-like monocytes promote cachexia in cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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