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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1630311

This article is part of the Research TopicInnovative Strategies for Overcoming Resistance in Tumor Angiogenesis TherapiesView all 6 articles

KCTD10 inhibits lung cancer metastasis and angiogenesis via ubiquitin-mediated β-catenin degradation

Provisionally accepted
Zihao  YinZihao Yin1Shengwen  LongShengwen Long1Hao  ZhouHao Zhou1Mi  OuyangMi Ouyang1Qinghao  WangQinghao Wang1Jun  HeJun He2Rongyu  SuRongyu Su1Zhiwei  LiZhiwei Li1Xiaofeng  DingXiaofeng Ding1*Shuanglin  XiangShuanglin Xiang1*
  • 1Hunan Normal University, Changsha, China
  • 2Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, chang sha, China

The final, formatted version of the article will be published soon.

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 Armidillo 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.

Keywords: KCTD10, Lung cancer metastasis, specific Kctd10 knockout, β-catenin, PD-1, M6A

Received: 17 May 2025; Accepted: 28 Jul 2025.

Copyright: © 2025 Yin, Long, Zhou, Ouyang, Wang, He, Su, Li, Ding and Xiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Xiaofeng Ding, Hunan Normal University, Changsha, China
Shuanglin Xiang, Hunan Normal University, Changsha, China

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