Department of Integration of Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.
Cells. 2022 Sep 29;11(19):3067. doi: 10.3390/cells11193067.
Hyperactivation of Wnt signaling is crucial in tumor formation. Fully elucidating the molecular details of how the cancer-specific Wnt signaling pathway is activated or contributes to tumorigenesis will help in determining future treatment strategies. Here, we aimed to explore the contribution of CUEDC2, a novel CUE-domain-containing protein, to the activation of Wnt signaling and the tumorigenesis of triple-negative breast cancer (TNBC) and to determine the underlying mechanisms. TNBC patient samples and disease-free survival (DFS) data were used to determine the association between CUEDC2 and TNBC progression. The effects of CUEDC2 on TNBC were examined in TNBC cells in vitro and in subcutaneous xenograft tumors in vivo. Gene knockdown, immunoprecipitation plus liquid chromatography-tandem mass spectrometry, pull-down, co-immunoprecipitation, localized surface plasmon resonance, and nuclear translocation analysis were used to uncover the mechanisms of CUEDC2 in regulating Wnt signaling and TNBC development. CUEDC2 is sufficient to maintain the hyperactivation of Wnt signaling required for TNBC tumorigenesis. The contribution of CUEDC2 plays a major role in determining the outcome of oncogenic Wnt signaling both in vitro and in vivo. Mechanistically, the CUE domain in CUEDC2 directly bound to the ARM (7-9) domain in β-catenin, promoted β-catenin nuclear translocation and enhanced the expression of β-catenin targeted genes. More importantly, an 11-amino-acid competitive peptide targeting the CUE domain in CUEDC2 blocked the interactions of CUEDC2 and β-catenin and abrogated the malignant phenotype of TNBC cells in vitro and in vivo. We observed that TNBC patients who exhibited higher levels of CUEDC2 showed marked hyperactivation of the Wnt signaling pathway and poor clinical outcomes, highlighting the clinical relevance of our findings. CUEDC2 promotes TNBC tumor growth by enhancing Wnt signaling through directly binding to β-catenin and accelerating its nuclear translocation. Targeting the interactions of CUEDC2 and β-catenin may be a valuable strategy for combating TNBC.
Wnt 信号的过度激活在肿瘤形成中至关重要。充分阐明癌症特异性 Wnt 信号通路如何被激活或有助于肿瘤发生的分子细节将有助于确定未来的治疗策略。在这里，我们旨在探索 CUEDC2（一种新型的 CUE 结构域蛋白）在 Wnt 信号激活和三阴性乳腺癌（TNBC）肿瘤发生中的作用，并确定其潜在机制。使用 TNBC 患者样本和无病生存（DFS）数据来确定 CUEDC2 与 TNBC 进展之间的关联。在体外 TNBC 细胞中和体内皮下异种移植肿瘤中检查 CUEDC2 对 TNBC 的影响。使用基因敲低、免疫沉淀加液相色谱-串联质谱、下拉、共免疫沉淀、局部表面等离子体共振和核转位分析来揭示 CUEDC2 调节 Wnt 信号和 TNBC 发展的机制。CUEDC2 足以维持 TNBC 肿瘤发生所需的 Wnt 信号的过度激活。CUEDC2 的贡献在体外和体内都在确定致癌 Wnt 信号的结果方面起着主要作用。机制上，CUEDC2 中的 CUE 结构域直接与 β-连环蛋白的 ARM（7-9）结构域结合，促进 β-连环蛋白核易位并增强 β-连环蛋白靶向基因的表达。更重要的是，针对 CUEDC2 中的 CUE 结构域的 11 个氨基酸竞争肽阻断了 CUEDC2 和 β-连环蛋白的相互作用，并消除了体外和体内 TNBC 细胞的恶性表型。我们观察到，表现出更高 CUEDC2 水平的 TNBC 患者表现出明显的 Wnt 信号通路过度激活和不良的临床结局，突出了我们研究结果的临床相关性。CUEDC2 通过直接结合 β-连环蛋白并加速其核易位来增强 Wnt 信号，从而促进 TNBC 肿瘤生长。靶向 CUEDC2 和 β-连环蛋白的相互作用可能是对抗 TNBC 的一种有价值的策略。
