Wang Huifen, Hu Jia, Wang Di, Cai Yudie, Zhu Weiwei, Deng Rui, Zhang Yize, Dong Zihui, Yang Zhe, Xiao Juan, Li Ang, Liu Zhibo
Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Cell Death Differ. 2025 Apr 2. doi: 10.1038/s41418-025-01498-4.
Selective autophagy is a finely regulated degradation pathway that can either promote or suppress cancer progression depending on its specific target cargoes. In this study, we report that transmembrane 9 superfamily member 1 (TM9SF1) suppresses colorectal cancer metastasis via selective autophagic degradation of Vimentin. Tm9sf1 knockout significantly increases tumor numbers and size, as well as enhances tumor invasion in colorectal cancer model. In vitro and in vivo phenotypical analyses reveal that TM9SF1 functions as a metastasis suppressor in colorectal cancer. Mechanistically, TM9SF1 facilitates the K63-linked ubiquitination of Vimentin by the E3 ligase TRIM21. The K63-linked ubiquitination of Vimentin serves as a recognition signal for autophagic degradation mediated by autophagic cargo receptor Tollip. Consequently, the downregulation of Vimentin results in a decreased number of F-actin-rich stress fibers and filopodium-like protrusions, ultimately inhibiting colorectal cancer metastasis. Moreover, TM9SF1 is downregulated in colorectal cancer patients with advanced stage compared to those with early stage and associated with favorable prognosis. Overall, our findings identify a novel TM9SF1-TRIM21-Vimentin-Tollip pathway involved in colorectal cancer metastasis, which may provide promising therapeutic targets for the treatment of metastatic colorectal cancer.
选择性自噬是一种精细调控的降解途径，根据其特定的靶标货物，它既可以促进也可以抑制癌症进展。在本研究中，我们报告跨膜9超家族成员1（TM9SF1）通过对波形蛋白的选择性自噬降解来抑制结直肠癌转移。在结直肠癌模型中，Tm9sf1基因敲除显著增加肿瘤数量和大小，并增强肿瘤侵袭。体外和体内表型分析表明，TM9SF1在结直肠癌中起转移抑制作用。机制上，TM9SF1促进E3连接酶TRIM21介导的波形蛋白的K63连接泛素化。波形蛋白的K63连接泛素化作为自噬货物受体Tollip介导的自噬降解的识别信号。因此，波形蛋白的下调导致富含F-肌动蛋白的应力纤维和丝状伪足样突起数量减少，最终抑制结直肠癌转移。此外，与早期结直肠癌患者相比，晚期患者中TM9SF1表达下调，且与良好预后相关。总体而言，我们的研究结果确定了一条参与结直肠癌转移的新型TM9SF1-TRIM21-波形蛋白-Tollip途径，这可能为转移性结直肠癌的治疗提供有前景的治疗靶点。
