IKKα kinase coordinates BRD4 and STAT3 signaling to subvert DNA damage-based anticancer therapy

Abstract

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