Inhibition of ISG15 Enhances the Anti-Cancer Effect of Trametinib in Colon Cancer Cells

BACKGROUND: Colon cancer is one of the most common cancers worldwide. IFN-stimulated gene 15 (ISG15), a ubiquitin-like molecule, is strongly up-regulated by type I interferon as a crucial response to a variety of microbial and cellular stress stimuli. However, the role of ISG15 in colon cancer remains unclear. METHODS: The expression of ISG15 in colon cancer tissues and cell lines was detected by using Western blotting and immunohistochemistry. ISG15 expression levels of colon cancer cells treated with trametinib was verified by using the data downloaded from the Gene Expression Omnibus (GEO) databases, quantitative real-time PCR analysis and Western blots assays. ISG15-siRNA was used to silence ISG15 in colon cancer cell line to determine the roles of ISG15 in colon cancer cell proliferation. RESULTS: ISG15 was highly expressed in colon cancer tissues and ISG15 upregulation was closely associated with poor prognoses in colon cancer patients. Enhanced ISG15 expression promoted the migration and proliferation of colon cancer cells in vitro, while ISG15 knockdown decreased cell proliferation and metastasis. In addition, we first found that the mRNA and protein expression of ISG15 were up-regulated following trametinib treatment. Further investigation showed that ISG15 knockdown could enhance the anti-cancer effect of trametinib in colon cancer cells. CONCLUSION: We proposed an interesting possibility that ISG15 may be a prognostic bio-marker, and the combined targeting of ISG15 and MEK might be a promising therapeutic strategy for colon cancer.