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

ABSTRACT: 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

SUBMITTER: Dr. Lluis Espinosa 

PROVIDER: S-SCDT-10_15252-EMBJ_2023114719 | biostudies-other |

REPOSITORIES: biostudies-other