EDARADD promotes colon cancer progression by suppressing E3 ligase Trim21-mediated ubiquitination and degradation of Snail

被引:16
作者
Yang, Jiani [1 ]
Liao, Yuanyu [1 ]
Wang, Bojun [1 ,3 ]
Cui, Luying [1 ]
Yu, Xuefan [1 ]
Wu, Feng [5 ,6 ]
Zhang, Yanqiao [1 ,3 ,4 ,5 ]
Liu, Ruiqi [2 ,7 ]
Yao, Yuanfei [1 ,4 ,5 ]
机构
[1] Harbin Med Univ, Canc Hosp, Dept Gastrointestinal Med Oncol, Harbin, Heilongjiang, Peoples R China
[2] Sun Yat Sen Univ, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Dept Radiat Oncol,Canc Ctr, Guangzhou 510060, Peoples R China
[3] Harbin Med Univ, Clin Res Ctr Colorectal Canc Heilongjiang, Canc Hosp, Harbin 150080, Peoples R China
[4] Harbin Med Univ, Key Lab Tumor Immunol Heilongjiang, Canc Hosp, Harbin 150080, Peoples R China
[5] Heilongjiang Acad Med Sci, Translat Med Res & Cooperat Ctr Northern China, Harbin 150080, Peoples R China
[6] Harbin Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Harbin 150000, Peoples R China
[7] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, Dept Radiat Oncol, State Key Lab Oncol South China,Canc Ctr, Guangzhou, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
Colon cancer; EDARADD; EMT; PPARa; Trim21; Ubiquitination; NF-KAPPA-B; ECTODERMAL DYSPLASIA; COLORECTAL-CANCER; EXPRESSION; TRIM21; BETA; INFLAMMATION; PATHWAYS; GROWTH; ALPHA;
D O I
10.1016/j.canlet.2023.216427
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumor cell migration, specifically epithelial-mesenchymal transition (EMT), serves as a key contributor to treatment failure in colon cancer patients. However, the limited comprehension of its genetic and biological aspects presents challenges for its investigation. EDAR-associated death domain (EDARADD), an important TNFR superfamily member, is elevated in colon cancer. However, it remains unclear about the exact role of EDARADD in the progression of colon cancer metastasis. In this study, we initially demonstrated that both protein and mRNA levels of EDDARADD are elevated in colon cancer tissues and cells, associated with reduced overall survival. Furthermore, functional experiments demonstrated that EDARADD promotes colon cancer cell proliferation and participates in EMT both in vitro and vivo. Mechanistically, Co-IP verified EDARADD could stabilize Snail1 by interacting with E3 ubiquitin ligase Trim21 to inhibit ubiquitination of Snail1. Interestingly, RNA-seq and ubiquitination assay revealed EDARADD's dual downregulation of Trim21 expression at the translational level via Cul1-mediated ubiquitin degradation, and at the transcriptional level through PPARa regulation. Moreover, EDARADD activates NF-kappa B signaling and experiences feedback transcriptional regulation by p65. In conclusion, this study highlights the signal pathway of EDARADD-PPARa-Trim21-Snail1-EMT and a feedback regulation of NF-kappa B signaling on EDARADD, which indicated EDARADD as an emerging therapeutic target for colon cancer.
引用
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页数:17
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