TRIM58 functions as a tumor suppressor in colorectal cancer by promoting RECQL4 ubiquitination to inhibit the AKT signaling pathway

Abstract

Abstract Background This study aimed to investigate the underlying molecular mechanisms of TRIM58 in the development of colorectal cancer (CRC). CRC is one of the most common cancers of the digestive tract worldwide. The ubiquitin–proteasome system regulates many oncogenic or tumor-suppressive proteins. TRIM58, an E3 ubiquitin ligase and a member of the tripartite motif protein family, is a potential prognostic marker that indicates poor prognosis in cancer. Currently, the precise molecular mechanisms for the TRIM58-mediated CRC progression remain unclear. Methods To examine the effects of TRIM58 on cell viability, cell cycle progression, and apoptosis in CRC, Cell Counting Kit-8 and flow cytometry assays were employed. The AKT inhibitor LY294002 was used to examine the effects of AKT signaling on TRIM58-mediated cell viability, cell cycle progression, and apoptosis in CRC. Additionally, Co-IP and ubiquitination assays were used to examine the correlation between TRIM58 and RECQL4. Results TRIM58 overexpression inhibited CRC cell viability and promoted cell cycle arrest and apoptosis, in which the TRIM58 knockdown demonstrated inversed effects via the AKT signaling pathway. TRIM58 inhibited RECQL4 protein levels through its ubiquitin ligase activity, and RECQL4 overexpression inhibited TRIM58 overexpression-mediated CRC cell viability, cell cycle progression, and apoptosis. The downregulation of TRIM58 and upregulation of RECOL4 were observed in human CRC tissue, and TRIM58 demonstrated antitumor effects in CRC-induced tumor growth in a mouse model. Conclusions TRIM58 acts as a tumor suppressor in CRC through the promotion of RECQL4 ubiquitination and inhibition of the AKT signaling pathway and may be investigated for the successful treatment of CRC.