Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival
Articolo
Data di Pubblicazione:
2017
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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all)
Elenco autori:
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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