TY - JOUR
T1 - BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer
AU - Conciatori, Fabiana
AU - Bazzichetto, Chiara
AU - Amoreo, Carla Azzurra
AU - Sperduti, Isabella
AU - Donzelli, Sara
AU - Diodoro, Maria Grazia
AU - Buglioni, Simonetta
AU - Falcone, Italia
AU - Shirasawa, Senji
AU - Blandino, Giovanni
AU - Ferretti, Gianluigi
AU - Cognetti, Francesco
AU - Milella, Michele
AU - Ciuffreda, Ludovica
N1 - Funding Information:
This work was supported in part by grants from “Fondazione AIRC per la Ricerca sul Cancro” (Ludovica Ciuffreda, IG 18622) and “Bando Interno Ricerca Corrente IRE 2018”. Fabiana Conciatori and Chiara Bazzichetto were supported by an AIRC fellowship for Italy. The authors wish to thank IRCCS Scientific Director office for supporting the manuscript.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Inflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.
AB - Inflammation might substantially contribute to the limited therapeutic success of current systemic therapies in colorectal cancer (CRC). Amongst cytokines involved in CRC biology, the proinflammatory chemokine IL-8 has recently emerged as a potential prognostic/predictive biomarker. Here, we show that BRAF mutations and PTEN-loss are associated with high IL-8 levels in CRC models in vitro and that BRAF/MEK/ERK, but not PI3K/mTOR, targeting controls its production in different genetic contexts. In particular, we identified a BRAF/ERK2/CHOP axis affecting IL-8 transcription, through regulation of CHOP subcellular localization, and response to targeted inhibitors. Moreover, RNA Pol II and an open chromatin status in the CHOP-binding region of the IL-8 gene promoter cooperate towards increased IL-8 expression, after a selective BRAF inhibition. Overall, our data show that IL-8 production is finely and differentially regulated depending on the tumor genetic context and might be targeted for therapeutic purposes in molecularly defined subgroups of CRC patients.
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U2 - 10.1038/s42003-020-01263-y
DO - 10.1038/s42003-020-01263-y
M3 - Article
C2 - 33004975
AN - SCOPUS:85091768016
VL - 3
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 546
ER -