BRAF status modulates Interelukin-8 expression through a CHOP-dependent mechanism in colorectal cancer.
Blotting, Western
Cell Line, Tumor
Colorectal Neoplasms
/ metabolism
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic
Humans
Interleukin-8
/ metabolism
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Mutagenesis, Site-Directed
Proto-Oncogene Proteins B-raf
/ metabolism
RNA Polymerase II
/ metabolism
Signal Transduction
Transcription Factor CHOP
/ metabolism
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
01 10 2020
01 10 2020
Historique:
received:
30
07
2019
accepted:
31
08
2020
entrez:
2
10
2020
pubmed:
3
10
2020
medline:
22
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33004975
doi: 10.1038/s42003-020-01263-y
pii: 10.1038/s42003-020-01263-y
pmc: PMC7530707
doi:
Substances chimiques
CXCL8 protein, human
0
DDIT3 protein, human
0
Interleukin-8
0
Transcription Factor CHOP
147336-12-7
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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