TRIM58 suppresses the tumor growth in gastric cancer by inactivation of β-catenin signaling via ubiquitination

Abstract

Objective: To investigate and define the underlying molecular mechanism of tripartite motif-containing 58 (TRIM58) in regulating the tumor growth of gastric cancer (GC). Methods: TRIM58 expression in GC tissues and cells was detected by real-time PCR and Western blot, followed by lentiviral-induced overexpression or knockdown of TRIM58. Subsequently, CCK8, BrdU-ELISA, flow cytometry, immunoprecipitation, in vitro animal experiments and immunochemistry were performed to explore the function of TRIM58. Western blotting was used to detect β-catenin, C-myc, Cyclin D1, and survivin expression. Results: TRIM58 expression was significantly reduced in tumor tissues of GC patients and GC cell lines, whereas β-catenin, C-myc, Cyclin D1, and survivin were highly expressed. Overexpression of TRIM58 in GC cells resulted in decreases in β-catenin, C-myc, Cyclin D1, and survivin protein expression and significantly suppressed proliferation by preventing cell-cycle progression and promoting cell apoptosis. Conversely, TRIM58 knockdown resulted in the opposite effects. Furthermore, the effect of TRIM58 knockdown on GC cells was potently reversed by a β-catenin inhibitor, XAV939. Immunoprecipitations showed the interaction between TRIM58 and β-catenin, and TRIM58 overexpression significantly enhanced β-catenin degradation. In addition, we found a significant decrease in the growth and weight of tumors and an increase in tumor cell apoptosis in TRIM58-overexpression nude mice, which were also accompanied by reduced β-catenin expression. Conclusions: These data suggest that TRIM58 may function as a tumor suppressor in GC and potentially suppress the tumor growth of gastric cancer by inactivation of β-catenin signaling via ubiquitination.

Silencing of the TRIM58 Gene by Aberrant Promoter Methylation is Associated with a Poor Patient Outcome and Promotes Cell Proliferation and Migration in Clear Cell Renal Cell Carcinoma

“…In the previous series of research, we identified some tumor-specifically methylated genes in RCC, such as DLC1, DLEC1, IRF8, ADAMTS18 ( Zhang et al, 2007 ; Zhang et al, 2010 ; Zhang et al, 2014 ). TRIM58, a member of the TRIM family, has been reported to play a tumor suppressive role and to be regulated by DNA methylation in lung cancer, colorectal cancer, and gastric cancer ( Kajiura et al, 2017 ; Liu M. et al, 2018 ; Liu et al, 2020 ). However, its DNA methylation status and biological function in ccRCC remained unclear.…”

“…Studies have revealed that the TRIM58 gene is hypermethylated and downregulated in a variety of malignancies including lung cancer, liver cancer, and pancreatic ductal adenocarcinoma ( Tao et al, 2011 ; Kajiura et al, 2017 ; Xu et al, 2019 ). Moreover, TRIM58 protein can inhibit proliferation and invasion in gastrointestinal cancer cells, indicating the tumor-suppressive role in such cancers ( Liu M. et al, 2018 ; Liu et al, 2020 ). However, the direct methylation–expression pattern and biological function of TRIM58 in ccRCC remains unclear.…”

Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma

“…Up to now, only two TRIM members— TRIM29 and TRIM58 which both exert opposing effects on tumors of the GI tract—have been identified to act mainly through modulation of Wnt/β-catenin signaling [ 37 , 71 , 77 ]. TRIM29 , a member of the group of RING-less TRIMs, acts as a tumor promoting factor in CRC as implicated by the fact that increased expression levels of TRIM29 observed in CRC patient specimens positively correlates with lymph node metastasis.…”

“…Similar tumor suppressive effects mainly related to an inactivation of β-catenin by TRIM58 have been demonstrated in gastric cancer (GC) cell lines. Accordingly, TRIM58 overexpression in GC cells caused a significant increase in β-catenin ubiquitination followed by its proteasomal degradation ( Figure 2 B) [ 77 ]. Collectively, these studies implicate that TRIM58 exerts tumorsuppressive activities in the GI tract mainly through inactivation of Wnt/β-catenin signaling.…”

“…Mechanistically, the TRIM58 -induced inhibition of invasion was mainly achieved through the negative regulation of β-catenin and subsequent downregulation of Snail and Slug transcription factors which together lead to the stabilization of cell–cell adhesion and basement membrane integrity [ 37 ]. To answer the question whether the reduction in Wnt/β-catenin signaling does mainly result from TRIM58 -dependent ubiquitination and degradation by the proteasome as reported for GC cells [ 77 ] requires further investigation.…”