title: A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer.
abstract: Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.
authors.affiliation: Institut Municipal d'Investigacions Mèdiques, Institut Hospital del Mar d'Investigacions Mèdiques, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain.
authors.forename: Pol
authors.initials: P
authors.lastname: Margalef
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fernández-Majada
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Ricard
authors.initials: R
authors.lastname: Garcia-Carbonell
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: María
authors.initials: M
authors.lastname: Martínez-Iniesta
authors.forename: Jordi
authors.initials: J
authors.lastname: Villà-Freixa
authors.forename: Mari Carmen
authors.initials: MC
authors.lastname: Mulero
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.forename: Ferran
authors.initials: F
authors.lastname: Torres
authors.forename: Marty W
authors.initials: MW
authors.lastname: Mayo
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.forename: Lluis
authors.initials: L
authors.lastname: Espinosa
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D006657:Histones; C491731:IKBKG protein, human; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase; D002403:Cathepsins