KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation
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 imp...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1630311/full |
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| author | Zihao Yin Zihao Yin Shengwen Long Shengwen Long Hao Zhou Hao Zhou Mi Ouyang Mi Ouyang Qinghao Wang Qinghao Wang Jun He Rongyu Su Zhiwei Li Zhiwei Li Xiaofeng Ding Xiaofeng Ding Xiaofeng Ding Shuanglin Xiang Shuanglin Xiang |
| author_facet | Zihao Yin Zihao Yin Shengwen Long Shengwen Long Hao Zhou Hao Zhou Mi Ouyang Mi Ouyang Qinghao Wang Qinghao Wang Jun He Rongyu Su Zhiwei Li Zhiwei Li Xiaofeng Ding Xiaofeng Ding Xiaofeng Ding Shuanglin Xiang Shuanglin Xiang |
| author_sort | Zihao Yin |
| collection | DOAJ |
| description | 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 in vitro and in vivo. 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 (Kctd10flox/floxCDH5CreERT2/+) promoted lung cancer metastasis and tumor angiogenesis through β-catenin signaling. Finally, we identified METTL14- mediated N6-methyladenosine (m6A) 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. |
| format | Article |
| id | doaj-art-6795f156740a431bb8fd997bcff391a7 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-6795f156740a431bb8fd997bcff391a72025-08-20T04:02:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16303111630311KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradationZihao Yin0Zihao Yin1Shengwen Long2Shengwen Long3Hao Zhou4Hao Zhou5Mi Ouyang6Mi Ouyang7Qinghao Wang8Qinghao Wang9Jun He10Rongyu Su11Zhiwei Li12Zhiwei Li13Xiaofeng Ding14Xiaofeng Ding15Xiaofeng Ding16Shuanglin Xiang17Shuanglin Xiang18The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaHunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaInstitute of Interdisciplinary Studies, Hunan Normal University, Changsha, ChinaPeptide and Small Molecule Drug R&D Platform, Furong Laboratory, Hunan Normal University, Changsha, ChinaThe National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, ChinaLung 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 in vitro and in vivo. 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 (Kctd10flox/floxCDH5CreERT2/+) promoted lung cancer metastasis and tumor angiogenesis through β-catenin signaling. Finally, we identified METTL14- mediated N6-methyladenosine (m6A) 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1630311/fullKCTD10lung cancer metastasisspecific Kctd10 knockoutβ-cateninPD-1M6A |
| spellingShingle | Zihao Yin Zihao Yin Shengwen Long Shengwen Long Hao Zhou Hao Zhou Mi Ouyang Mi Ouyang Qinghao Wang Qinghao Wang Jun He Rongyu Su Zhiwei Li Zhiwei Li Xiaofeng Ding Xiaofeng Ding Xiaofeng Ding Shuanglin Xiang Shuanglin Xiang KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation Frontiers in Immunology KCTD10 lung cancer metastasis specific Kctd10 knockout β-catenin PD-1 M6A |
| title | KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation |
| title_full | KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation |
| title_fullStr | KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation |
| title_full_unstemmed | KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation |
| title_short | KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation |
| title_sort | kctd10 inhibits lung cancer metastasis and angiogenesis via ubiquitin mediated β catenin degradation |
| topic | KCTD10 lung cancer metastasis specific Kctd10 knockout β-catenin PD-1 M6A |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1630311/full |
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