학술논문
IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.
Document Type
Academic Journal
Author
Pecharromán I; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Solé L; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Álvarez-Villanueva D; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.; Lobo-Jarne T; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Alonso-Marañón J; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Bertran J; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Faculty of Science and Technology, University of Vic - Central University of Catalonia, Vic, Spain.; Guillén Y; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Montoto Á; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Martínez-Iniesta M; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.; García-Hernández V; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Giménez G; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Salazar R; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain.; Santos C; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain.; Garrido M; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Borràs E; Proteomics Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.; Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain.; Sabidó E; Proteomics Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.; Proteomics Unit, Universitat Pompeu Fabra, Barcelona, Spain.; Bonfill-Teixidor E; Vall d'Hebron Institute of Oncology (VHIO), CIBERONC, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.; Iurlaro R; Vall d'Hebron Institute of Oncology (VHIO), CIBERONC, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.; Seoane J; Vall d'Hebron Institute of Oncology (VHIO), CIBERONC, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.; Villanueva A; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.; Xenopat S.L., Parc Cientific de Barcelona (PCB), Barcelona, Spain.; Iglesias M; Department of Pathology, Institut Mar d'Investigacions Mèdiques, CIBERONC, Universitat Autònoma de Barcelona, Barcelona, Spain.; Bigas A; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.; Josep Carreras Leukemia Research Institute, Badalona, Spain.; Espinosa L; Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
Subject
Language
English
Abstract
Activation of the IκB kinase (IKK) complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification of downstream effectors other than NF-κB has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV treatment revealed that phosphorylation of BRD4 by IKK-α is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK-α induces the NF-κB-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK-α abrogation results in defective BRD4 and STAT3 functions and consequently irreparable DNA damage and apoptotic cell death upon different stimuli. Simultaneous inhibition of BRAF-dependent IKK-α activity, BRD4, and the JAK/STAT pathway enhanced the therapeutic potential of 5-fluorouracil combined with irinotecan in CRC cells and is curative in a chemotherapy-resistant xenograft model. Finally, coordinated expression of LIF and IKK-α is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-α, BRD4, and JAK/STAT signaling with clinical relevance.
(© 2023 The Authors.)
(© 2023 The Authors.)