Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Barcelona, Spain.
Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.
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.
IKK 激酶（IKK）复合物的激活经常与结直肠癌（CRC）的发生和发展有关。然而，除了 NF-κB 之外，其他下游效应物的鉴定仍然难以捉摸。在这里，在 UV 处理后分析 CRC 细胞中 IKK 依赖性底物时，发现 IKK-α 对 BRD4 的磷酸化对于 DNA 损伤时其在靶基因上的染色质结合是必需的。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 结合以及募集到特定的靶基因。IKK-α 的缺失导致 BRD4 和 STAT3 功能缺陷，从而导致在不同刺激下不可修复的 DNA 损伤和细胞凋亡。同时抑制依赖 BRAF 的 IKK-α 活性、BRD4 和 JAK/STAT 通路增强了氟尿嘧啶联合伊立替康在 CRC 细胞中的治疗潜力，并在化疗耐药的异种移植模型中具有治愈作用。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 信号之间具有临床相关性的功能联系。
