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.

中文翻译：

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IκB 激酶-α 协调 BRD4 和 JAK/STAT 信号传导，颠覆基于 DNA 损伤的抗癌疗法

IκB 激酶 (IKK) 复合物的激活经常与结直肠癌 (CRC) 的发生和进展相关。然而，除 NF-κB 之外的下游效应子的鉴定仍然难以捉摸。在这里，对 UV 处理后 CRC 细胞中 IKK 依赖性底物的分析表明，在 DNA 损伤时，IKK-α 磷酸化 BRD4 是其染色质与靶基因结合所必需的。此外，IKK-α 诱导细胞因子 LIF 的 NF-κB 依赖性转录，导致 STAT3 激活、与 BRD4 关联并招募到特定靶基因。IKK-α 的废除会导致 BRD4 和 STAT3 功能缺陷，从而在不同刺激下导致不可修复的 DNA 损伤和细胞凋亡。同时抑制 BRAF 依赖性 IKK-α 活性、BRD4 和 JAK/STAT 通路增强了 5-氟尿嘧啶联合伊立替康在 CRC 细胞中的治疗潜力，并且在化疗耐药异种移植模型中具有疗效。最后，LIF 和 IKK-α 的协调表达是 CRC 患者预后不良的标志。我们的数据揭示了 IKK-α、BRD4 和 JAK/STAT 信号传导之间具有临床相关性的功能联系。