IκB kinase- coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anti-cancer therapy

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-B has remained elusive. Here, analysis of IKK-dependent substrates in CRC cells after UV-treatment revealed that phosphorylation of BRD4 by IKK- is required for its chromatin-binding at target genes upon DNA damage. Moreover, IKK- induces the NF-B-dependent transcription of the cytokine LIF, leading to STAT3 activation, association with BRD4 and recruitment to specific target genes. IKK- 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- 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- is a poor prognosis marker for CRC patients. Our data uncover a functional link between IKK-, BRD4 and JAK/STAT signaling with clinical relevance.