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

Abstract

To investigate the underlying molecular mechanism of tripartite motif-containing 58 (TRIM58) in the development of clear cell renal cell carcinoma (ccRCC), we explored TRIM58 expression and methylation in tumor tissues and the association with clinicopathological features and prognosis of tissue samples; Moreover, we examined the direct gene transcription of TRIM58-specific DNA demethyltransferase (TRIM58-TET1) by the CRISPR-dCas9 fused with the catalytic domain of TET1 and the biological functions in RCC cells. In this study, we demonstrate that TRIM58 is frequently downregulated by promoter methylation in ccRCC tissues, associated significantly with tumor nuclear grade and poor patient survival. TRIM58-TET1 directly induces demethylation of TRIM58 CpG islands, and activates TRIM58 transcription in RCC cell lines. Besides, DNA demethylation of TRIM58 by TRIM58-TET1 significantly inhibits cell proliferation and migration Overall, our results demonstrate that TRIM58 is inactivated by promoter methylation, associates with tumor nuclear grade and poor survival, and TRIM58 DNA demethylation could directly activate TRIM58 transcription and inhibit cell proliferation and migration in RCC cell lines.

Profiling genetically driven alternative splicing across the Indonesian Archipelago

“…phagocytosis (e.g., VAV3, NCF2, C4BPA, DYSF, MARCO, CD302 ), regulation of innate immune response (e.g., GBP2, ADAR, FCRL3, IFI16, AIM2, CFH ), and interleukin-1 beta production (e.g., IFI16, AIM2, NLRC4, CASP8, GHRL, CX3CR1 ), highlighting the impact of splicing on immune-related genes (Supplementary Figure 3, Table S6). Indeed, some of the strongest sQTL signals are present in immune-related genes such as TRIM58, which is additionally implicated in malignancies such as lung cancer, liver cancer, and pancreatic ductal adenocarcinoma [69][70][71][72], and is involved in innate immunity and cell proliferation [69,73], and ERMAP, which is a B7 family immune regulator that has been found…”

“…This observation is consistent with previous research suggesting that most variants that fall in close proximity to splice junctions influence splicing regulatory functions [67,68] GO enrichment analysis of sGenes (genes with a significant sQTL) revealed enrichment for numerous immune-related pathways, including: immune response-regulating signaling (e.g., THEMIS2, ERMAP, GBP2, VAV3, FCRL3, AIM2, FCGR3A), immune response-activating signaling (e.g., DENND1B, MAPKAPK2, CR1, NLRC4, NAGK, IFIH1, PRKCD), phagocytosis (e.g., VAV3, NCF2, C4BPA, DYSF, MARCO, CD302 ), regulation of innate immune response (e.g., GBP2, ADAR, FCRL3, IFI16, AIM2, CFH ), and interleukin-1 beta production (e.g., IFI16, AIM2, NLRC4, CASP8, GHRL, CX3CR1 ), highlighting the impact of splicing on immune-related genes (Supplementary Figure 3, Table S6). Indeed, some of the strongest sQTL signals are present in immune-related genes such as TRIM58, which is additionally implicated in malignancies such as lung cancer, liver cancer, and pancreatic ductal adenocarcinoma [69][70][71][72], and is involved in innate immunity and cell proliferation [69,73], and ERMAP, which is a B7 family immune regulator that has been found to promote the phagocytosis of tumor cells [74][75][76] and encodes the protein responsible for the Scianna blood group system [77] (Supplementary Figure 4).…”

Targeted DNA Demethylation: Vectors, Effectors and Perspectives

“…The tripartite-motif (TRIM) family proteins contribute to cancer initiation, progress, or therapy resistance, exhibiting tumor-suppressive functions: they are frequently downregulated by promoter methylation in cancerous tissues [155]. dCas9-TET1CD induced specific demethylation of TRIM58 in renal carcinoma cells (RCC) [156]. Promoter of the TMEM244 gene was demethylated to upregulate its expression in Sézary syndrome-an aggressive form of cutaneous T-cell lymphoma [157].…”

Predictive and Prognostic Value of TRIM58 Protein Expression in Patients with Breast Cancer Receiving Neoadjuvant Chemotherapy

“…17 Previous studies reported that TRIM58 served as tumor suppressor and conferred better survival in gastric cancer, thyroid cancer, colorectal cancer and renal cell carcinoma. [18][19][20][21] Our previous study identified that TRIM58 was highly expressed in drug-resistant breast-cancer cell strains and inactivated p53/p21 to promote chemoresistance by ubiquitination of DEAD-Box Helicase 3 X-Linked (DDX3) in breast cancer. 22 However, it remains unclear whether TRIM58 expression levels influence the individual clinical benefits of NAT.…”