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

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.

Glucose Metabolism Reprogramming in Bladder Cancer: Hexokinase 2 (HK2) as Prognostic Biomarker and Target for Bladder Cancer Therapy

“…In our cohort, GLUT1 expression was not limited to the hypoxic regions of the tissue samples, being equally present in the membranes of UBC cells located near to patent and mature blood vessels. In accordance with this, other studies have described positive [lysine deacetylase SIRT1 [53]] or negative [microRNA-218 [54], E3 ubiquitin-protein ligase TRIM38 [55]] regulators of GLUT1 expression in BC other than hypoxia. Nevertheless, the GLUT1 expression by the normoxic and/or hypoxic UBC cells showed a clear association with the aggressiveness parameters in our study, but no correlation with the survival rates was reached.…”

Glycolysis-Related SLC2A1 Is a Potential Pan-Cancer Biomarker for Prognosis and Immunotherapy

“…Additionally, the expression of SLC2A1 is significantly upregulated in higher pathologic stages in various cancers. Previous studies have reported that SLC2A1 is highly expressed in a variety of cancers, such as BLCA, LUAD, LIHC, CESC, COAD, OV, UCEC, BRCA, STAD, ESCA, and PAAD [ 11 , 12 , 13 , 14 , 15 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. These results are consistent with our research results.…”

Identification of Bladder Cancer Subtypes Based on Necroptosis-Related Genes, Construction of a Prognostic Model

“…He et al found that GSDMB could bind to STAT 3, thereby activating STAT 3 signaling in bladder cancer, and demonstrated that GSDM could interact with USP 24B to hinder the degradation of GSDMB in bladder cancer, thus the USP 24/GSDMB/STAT 3 axis could be a new signaling pathway for targeted bladder cancer therapy ( 29 ). Wang et al demonstrated that TRIM 38 plays an inhibitory role in the development of bladder cancer, and the TRIM 38/GLUT 1 axis is of great importance as a weak point for bladder cancer treatment ( 30 ). The relationship between the remaining three predictors and bladder cancer is not yet supported by relevant experimental evidence and literature; therefore, they may provide options for later investigators when studying potential therapeutic targets for bladder cancer.…”