TRIM50 Inhibits Gastric Cancer Progression by Regulating the Ubiquitination and Nuclear Translocation of JUP

Gastric cancer is one of the most frequent cancers in the world. Emerging clinical data show that ubiquitination system disruptions are likely involved in carcinoma genesis and progression. However, the precise role of ubiquitin (Ub)-mediated control of oncogene products or tumor suppressors in gastric cancer is unknown. Tripartite motif-containing 50 (TRIM50), an E3 ligase, was discovered by high-output screening of ubiquitination-related genes in tissues from patients with gastric cancer to be among the ubiquitination-related enzymes whose expression was most downregulated in gastric cancer. With two different databases, we verified that TRIM50 expression was lower in tumor tissues relative to normal tissues. TRIM50 also suppressed gastric cancer cell growth and migration in vitro and in vivo. JUP, a transcription factor, was identified as a new TRIM50 ubiquitination target by MS and coimmunoprecipitation experiments. TRIM50 increases JUP K63-linked polyubiquitination mostly at the K57 site. We discovered that the K57 site is critical for JUP nuclear translocation by prediction with the iNuLoC website and further studies. Furthermore, ubiquitination of the K57 site limits JUP nuclear translocation, consequently inhibiting the MYC signaling pathway. These findings identify TRIM50 as a novel coordinator in gastric cancer cells, providing a potential target for the development of new gastric cancer treatment strategies. IMPLICATIONS: TRIM50 regulates gastric cancer tumor progression, and these study suggest TRIM50 as a new cancer target.