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 / M. Segatto, R. Fittipaldi, F. Pin, R. Sartori, K. Dae Ko, H. Zare, C. Fenizia, G. Zanchettin, E.S. Pierobon, S. Hatakeyama, C. Sperti, S. Merigliano, M. Sandri, P. Filippakopoulos, P. Costelli, V. Sartorelli, G. Caretti. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8:1(2017 Dec 01).
|Titolo:||Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival|
CARETTI, GIUSEPPINA (Corresponding)
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
Settore BIO/13 - Biologia Applicata
Settore BIO/18 - Genetica
|Data di pubblicazione:||1-dic-2017|
|Data ahead of print / Data di stampa:||22-nov-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41467-017-01645-7|
|Appare nelle tipologie:||01 - Articolo su periodico|