IKKα kinase coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy

• DOI: 10.1101/2023.06.13.544711
• Publication Date: 2023-06-15T14:45:37Z
• Authors: Irene Pecharromán; Laura Solé; Daniel Álvarez-Vi...; Teresa Lobo-Jarne; Josune Alonso-Mar...; Joan Bertran; Yolanda Guillén; Ángela Montoto; María Martínez-In...; Violeta García-He...; Gemma Giménez; Ramon Salazar; Cristina Santos; Marta Garrido; Eva Borràs; Eduard Sabidó; Ester Bonfill-Tei...; Raffaella Iurlaro; Joan Seoane; Alberto Villanueva; Mar Iglesias; Anna Bigas; Lluís Espinosa
• Keywords: IκB kinase

SUMMARY Activation of the IKK kinase complex has recurrently been linked to colorectal cancer (CRC) initiation and progression. However, identification downstream effectors other than NF-κB remained elusive. Analysis IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKKα is required for chromatin-binding dynamics upon damage. Moreover, induces NF-κB-dependent transcription LIF leading STAT3 activation, association recruitment specific target genes. abrogation results in defective function irreparable DNA damage apoptotic cell death different stimuli. Simultaneous inhibition BRAF-dependent activity or JAK/STAT pathway enhanced therapeutic potential 5-FU plus irinotecan CRC cells, curative a chemotherapy-resistant xenograft model. Coordinated expression poor prognosis marker patients. Our data uncover functional link between IKKα, signaling with clinical relevance.