IκB激酶（IKK）复合物的激活与结直肠癌（CRC）的发生和发展反复关联。然而，除了NF-κB之外，对下游效应物质的鉴定一直是困难的。在这里，对CRC细胞在UV处理后，IKK依赖底物的分析揭示了在DNA损伤后，IKK-α对BRD4的磷酸化是其在目标基因上结合染色质所必需的。此外，IKK-α诱导了NF-κB依赖的细胞因子LIF的转录，导致STAT3的激活，与BRD4的结合并招募到特定的目标基因上。IKK-α的失活导致了BRD4和STAT3功能的缺陷，进而造成了不可修复的DNA损伤和在不同刺激下的细胞凋亡。对BRAF依赖的IKK-α活性、BRD4和JAK/STAT通路的同时抑制，增强了5-氟尿嘧啶联合伊立替康在CRC细胞中的治疗潜力，并在一个化疗耐药的异种移植模型中具有治疗作用。最后，LIF和IKK-α的协调表达是CRC患者预后不良的标志物。我们的数据揭示了IKK-α、BRD4和JAK/STAT信号传导之间具有临床意义的功能联系。© 2023 The Authors.

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.© 2023 The Authors.