IκB kinase-α coordinates BRD4 and JAK/STAT signaling to subvert DNA damage-based anticancer therapy.
Irene PecharrománLaura SoléDaniel Alvarez-VillanuevaTeresa Lobo-JarneJosune Alonso-MarañónJoan BertranYolanda GuillénÁngela MontotoMaría Martínez-IniestaVioleta García-HernándezGemma GiménezRamon SalazarCristina SantosMarta GarridoEva BorràsEduard SabidóEster Bonfill-TeixidorRaffaella IurlaroJoan SeoaneAlberto VillanuevaMar IglesiasAnna BigasLluís EspinosaPublished in: The EMBO journal (2023)
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.
Keyphrases
- dna damage
- poor prognosis
- cell death
- oxidative stress
- cell cycle arrest
- induced apoptosis
- dna repair
- signaling pathway
- long non coding rna
- genome wide
- end stage renal disease
- transcription factor
- protein kinase
- chronic kidney disease
- ejection fraction
- prognostic factors
- lps induced
- pi k akt
- bioinformatics analysis
- stem cells
- endoplasmic reticulum stress
- immune response
- big data
- combination therapy
- radiation therapy
- locally advanced
- rectal cancer
- artificial intelligence
- data analysis
- genome wide identification
- smoking cessation
- type iii
- deep learning