RING1 is an Integrin α5 E3 ubiquitin ligase and inhibits esophageal squamous cell carcinoma cell migration and metastasis
- Cell Signal. 2026 Oct:146:112631. doi: 10.1016/j.cellsig.2026.112631.
- 1. Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, China; Department of Clinical Medicine, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Integrated Traditional Chinese and Western Medicine in Senile Diseases Control, Yangzhou University, Yangzhou, Jiangsu 225001, China.
- 2. Department of Pharmacy, Suining People's Hospital, Xuzhou, Jiangsu 221200, China.
- 3. Department of Clinical Medicine, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Integrated Traditional Chinese and Western Medicine in Senile Diseases Control, Yangzhou University, Yangzhou, Jiangsu 225001, China.
- 4. Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu 225000, China; Department of Clinical Medicine, Faculty of Medicine, Key Laboratory of the Jiangsu Higher Education Institutions for Integrated Traditional Chinese and Western Medicine in Senile Diseases Control, Yangzhou University, Yangzhou, Jiangsu 225001, China. Electronic address: [email protected].
Esophageal squamous cell carcinoma (ESCC) is an extremely aggressive malignancy associated with dismal prognosis and high mortality, primarily due to metastasis, with cell migration being a critical component of the metastatic process. Ring finger protein 1 (RING1), an E3 ubiquitin Ligase, has been reported as an important regulator in tumorigenesis. However, its specific functions and substrates in ESCC remain to be elucidated. Here, we found that RING1 acted in a catalytic domain-dependent manner to inhibit ESCC cell migration, but had no effect on cell proliferation. Interestingly, we confirmed that RING1 inhibited cell adhesion, spreading, and migration by regulating Integrin α5/FAK pathway in ESCC. Mechanistically, we identified Integrin α5 as a new substrate of RING1. RING1 could bind and destabilize Integrin α5 via K11-linked ubiquitination. Overexpression of RING1 resulted in the degradation of Integrin α5 and suppressed cell migration in ESCC cells, especially under fibronectin-coated condition. Re-expression of Integrin α5 rescued RING1-mediated suppression of ESCC cell adhesion, spreading, and migration. Knockdown of Integrin α5 could abrogate RING1-mediated inhibitory effects on cell adhesion, spreading, migration, and tumor metastasis. Altogether, our findings provide new mechanistic insights into RING1-mediated inhibition of tumor metastasis via binding to Integrin α5, highlighting the RING1/Integrin α5/FAK axis as a promising target for the treatment of metastatic ESCC.