Yin Zihao, Long Shengwen, Zhou Hao, Ouyang Mi, Wang Qinghao, He Jun, Su Rongyu, Li Zhiwei, Ding Xiaofeng, Xiang Shuanglin
The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, China.
State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, China.
Front Immunol. 2025 Aug 12;16:1630311. doi: 10.3389/fimmu.2025.1630311. eCollection 2025.
Lung cancer remains a critical global health concern, characterized by the highest incidence and mortality rates among all cancers. Due to its heterogeneity and complexity, the molecular mechanism underlying lung cancer occurrence and progression needs to be further investigated. KCTD10 has been implicated in malignant phenotypes of several tumors, but the role of KCTD10 in lung cancer remains largely unexplored. In this study, we found that KCTD10 expression is significantly reduced in lung cancer tissues, and overexpression of KCTD10 could inhibit lung cancer progression both and . Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), and ubiquitination assays revealed that the BTB domain of KCTD10 interacts with Armadillo repeat domains 1-9 of β-catenin and facilitates ubiquitin-dependent degradation of β-catenin via the K48-linked ubiquitin chains, followed by the downregulation of the β-catenin downstream target gene PD-L1. Notably, the combined treatment of KCTD10 overexpression with anti-PD-1 antibodies exhibited a synergistic effect in suppressing lung cancer progression and brain metastatic colonization in mice. In addition, vascular endothelial cell-specific knockout of Kctd10 (Kctd10CDH5) promoted lung cancer metastasis and tumor angiogenesis through β-catenin signaling. Finally, we identified METTL14- mediated N6-methyladenosine (mA) modification within the coding sequence (CDS) region of KCTD10, which enhanced KCTD10 mRNA stability in a YTHDF2-dependent manner. These findings highlight KCTD10 as a critical regulator of lung cancer progression and the tumor microenvironment, suggesting its potential as a promising therapeutic target for lung cancer.
肺癌仍然是一个关键的全球健康问题，在所有癌症中发病率和死亡率最高。由于其异质性和复杂性，肺癌发生和进展的分子机制仍需进一步研究。KCTD10已被证明与多种肿瘤的恶性表型有关，但KCTD10在肺癌中的作用仍 largely unexplored。在本研究中，我们发现KCTD10在肺癌组织中的表达显著降低，KCTD10的过表达可以抑制肺癌的进展。免疫沉淀-质谱（IP-MS）、免疫共沉淀（Co-IP）和泛素化分析表明，KCTD10的BTB结构域与β-连环蛋白的犰狳重复结构域1-9相互作用，并通过K48连接的泛素链促进β-连环蛋白的泛素依赖性降解，随后下调β-连环蛋白下游靶基因PD-L1。值得注意的是，KCTD10过表达与抗PD-1抗体联合治疗在抑制小鼠肺癌进展和脑转移定植方面表现出协同作用。此外，血管内皮细胞特异性敲除Kctd10（Kctd10CDH5）通过β-连环蛋白信号促进肺癌转移和肿瘤血管生成。最后，我们鉴定了METTL14介导的KCTD10编码序列（CDS）区域内的N6-甲基腺苷（m6A）修饰，其以YTHDF2依赖性方式增强了KCTD10 mRNA的稳定性。这些发现突出了KCTD10作为肺癌进展和肿瘤微环境的关键调节因子，表明其作为肺癌有前景的治疗靶点的潜力。
