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

EMBO J. 2023 Nov 2;42(21):e114719. doi: 10.15252/embj.2023114719. Epub 2023 Sep 22.


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

Keywords: BRD4; IKK-α; LIF; STAT3; colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Humans
  • I-kappa B Kinase* / metabolism
  • Janus Kinases / genetics
  • NF-kappa B / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • STAT Transcription Factors
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • I-kappa B Kinase
  • NF-kappa B
  • Nuclear Proteins
  • Protein Serine-Threonine Kinases
  • Janus Kinases
  • STAT Transcription Factors
  • Tumor Necrosis Factor-alpha
  • BRD4 protein, human
  • Transcription Factors
  • Cell Cycle Proteins

Associated data

  • GEO/GSE196461