Abstract
Background Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). TRIM25, an E3-ubiquitin ligase, has been reported to play a vital role in tumorigenesis. This project aims to explore the function and mechanism of TRIM25 in regulating oxaliplatin resistance in colorectal cancer.Methods The expression of TRIM25 in colorectal cancer tissues were examined by publicly available dataset, Immunohistochemistry and western blot. Further survival analysis was conducted using Kaplan-Meier method. CCK8 assay, colony-formation assay, Annexin V-FITC /PI staining and xenograft tumor models were used for evaluating sensitivity of CRC cells to oxaliplatin. Sphere-formation assay, RT-PCR and limiting dilution assay were used to evaluate the influence of TRIM25 on stem cell properties of CRC cells. Co-immunoprecipitation, polyubiquitination assay and western bolt elucidate the mechanism by which TRIM25 regulates EZH2.Results Patients with high expression of TRIM25 have significantly higher recurrence rate (28.9% vs. 15.0%, P = 0.012) and worse disease-free survival (P = 0.006) than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited while TRIM25 overexpression enhanced CRC cells survival after oxaliplatin treatment. In addition, TRIM25 promotes stem cell properties of CRC cells both in vitro and in vivo (8 mice per group). Importantly, we demonstrated that TRIM25 inhibits the binding of E3-ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2 and promoting oxaliplatin resistance. Conclusions Our study provides evidence that TRIM25 is a novel epigenetic regulator of oxaliplatin resistance. Targeting TRIM25 might be a promising strategy for CRC treatment.
Copy number variation of E3 ubiquitin ligase genes in peripheral blood leukocyte and colorectal cancer