RNF180 Suppresses Methylation of ADAMTS9 DNA Promotor by Ubiquitinating DNMT3A Inhibiting Metastasis in Gastric Cancer

Abstract BACKGROUND: A disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9) is hypermethylated and inhibits the proliferation of various cancers. In this study, we demonstrated that the expression of ADAMTS9 was associated with the lymphatic metastasis of gastric cancer (GC) and elucidated the down- and upstream molecular pathways in GC progression. METHODS: The study explored the expression level, biological function, clinical application, and involved molecular mechanism of ADAMTS9 in GC. RESULTS: In 135 GC tissue samples, ADAMTS9 expression level was significantly correlated with the pN stage, the number of metastatic lymph nodes (LNs), and the overall survival of patients with GC. The in vitro and in vivo experiments showed that ADAMTS9 attenuated the viability and motile capacity of GC cells. Mechanistic investigations revealed that ADAMTS9 significantly inhibited the transcription of C–C motif chemokine ligand 5 (CCL5)/C–X–C motif chemokine ligand 11 (CXCL11). This effect impaired the migration and invasion in GC cells. This study revealed that the hypermethylation level in the promotor of ADAMTS9 gene was mainly mediated by DNA-methyltransferase(DNMT) 3A, which reduces ADAMTS9 expression in GC. Ring finger protein (RNF) 180 could promote DNMT3Aubiquitination and degradation, thereby restoring the ADAMTS9 expression in GC cells. CONCLUSIONS: ADAMTS9 expression is restored by the RNF180 via suppressing the promotor methylation of the ADAMTS9 gene. ADAMTS9 inhibits metastasis and improves the prognosis of patients with GC via CCL5/CXCL11-dependent pathway. Thus, ADAMTS9 should be considered as a predictor of LN metastasis and a therapeutic target in GC.