TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer

Abstract

Abstract Background Loss-of-function mutations or abnormal expressions of E ubiquitin ligases contributes to tumorigenesis. TRIM38 was reported to regulate immunity, inflammatory responses or apoptosis, but its roles in tumor progression remain inconclusive. This study aimed to investigate the functional roles of TRIM38 in bladder cancer to identify effective targets. Methods Firstly, the expression data of ubiquitination-associated genes were derived from the TCGA-BLCA cohort. Univariate Cox regression method was utilized to screen prognostic genes. Colony formation assay, Transwell assay, sphere formation assays were used to assess functional roles of TRIM38. TAP/MS assay was used to identify downstream substrates of TRIM38. Fresh clinical BLCA tissues were collected to evaluate the clinicopathological features of patients with different TRIM38 expression. The subcutaneous tumor models were established to determine the drug efficacy of BAY-876. Results A list of ubiquitination-associated signature was identified based on the screening in TCGA-BLCA cohort. Subsequent validations revealed that TRIM38 was a significant suppressor in tumors, which was expressed lowly in BLCA. Kaplan–Meier analysis and correlation analysis suggested that patients with low TRIM38 expressions had shorter survival time and advanced clinical characteristics. Targeting TRIM38 reinforced BLCA cells proliferation, migration and stemness. Mechanistically, TRIM38 interacted with GLUT1, thereby promoting its ubiquitinoylation and degradation. Furthermore, TRIM38 deficiency relied on accumulated GLUT1 proteins to enhance BLCA malignant features and cellular glycolytic capacity. We accordingly investigated the efficacy of GLUT1 inhibitor (BAY-876) in BLCA and determined its IC50 values across cell lines. Tumor xenograft models further validated that BAY-876 could effectively suppress the in vivo growth of TRIM38low/− BLCA. Conclusions Our results suggested that TRIM38 plays a tumor suppressive role in BLCA pathogenesis and TRIM38/GLUT1 axis is a therapeutic vulnerability for clinical treatment, which possessing great translational significance.

Keywords

• TRIM38
• GLUT1
• Glycolysis
• BAY-876
• Bladder cancer