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

SUMMARY 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-κB has remained elusive. Analysis of IKK-dependent substrates after UV-treatment revealed that BRD4 phosphorylation by IKKα is required for chromatin-binding dynamics upon damage. Moreover, IKKα induces the NF-κB-dependent transcription of LIF leading to STAT3 activation, association of BRD4 to STAT3 and recruitment to specific target genes. IKKα 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 IKKα activity or BRD4 and the JAK/STAT pathway enhanced the therapeutic potential of 5-FU plus irinotecan in CRC cells, and is curative in a chemotherapy-resistant CRC xenograft model. Coordinated expression of LIF and IKKα is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKKα, BRD4 and JAK/STAT signaling with clinical relevance.