TRIM25 Regulates Oxaliplatin Resistance in Colorectal Cancer by Promoting EZH2 Stability

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.

An Immune-Related Long Noncoding RNA Signature as a Prognostic Biomarker for Human Endometrial Cancer

“…For example, by regulating mitotic checkpoints and chromosome stability, TIF1c inhibits tumor progression [38]. Recently, epigenetic regulation was shown to play a vital role in the occurrence and development of tumors, such as regulating tumor resistance, proliferation, metastasis, and epithelial-mesenchymal transition [39][40][41][42][43][44]. Interestingly, prognostic model based on epigenetic regulation was constructed to predict patient prognosis, such as a prognostic model based on nine ferroptosis-related genes (ALOX15, CISD1, CS, GCLC, GPX4, SLC7A11, EMC2, G6PD, and ACSF2) that could predict the prognosis of breast cancer [45].…”

Growth arrest and DNA damage‐inducible alpha regulates muscle repair and fat infiltration through ATP synthase F1 subunit alpha

“…Given that ATP5A1 is a mitochondrial protein, we focused on TRIM25 in this study. TRIM25, as a member of the E3 ubiquitination ligase family, has been reported to regulate the ubiquitination of various proteins 37 . Here, we showed that GADD45A might recruit TRIM25 and increase the total ubiquitination and degradation of ATP5A1.…”

“…TRIM25, as a member of the E3 ubiquitination ligase family, has been reported to regulate the ubiquitination of various proteins. 37 Here, we showed that GADD45A might recruit TRIM25 and increase the total ubiquitination and degradation of ATP5A1. The biochemical link between GADD45A and ATP5A1 appears to be a critical pathogenic mechanism during the development of adipogenesis and skeletal muscle metabolic diseases.…”

RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ

“…We have reported for the first time that TRIM25 is the E3 ligase of RBPJ. Indeed, the oncogenic function of TRIM25 has also been reported in various tumors, including prostate cancer, 30 hepatocellular carcinoma, 31 and colorectal cancer 32 . We suspect that this is most likely to be related to the degradation of RBPJ and inhibition of the Notch1 signaling.…”