This article is the original of the Translational Medicine Network, please indicate the source for reprinting
Author: Rainbow
Summary: TRIM25 is a member of the TRIM protein family and is involved in tumorigenesis through substrate ubiquitination.
On February 2, the research team of Zhejiang University School of Medicine published an online paper entitled "TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by" in the journal Journal of Experimental & Clinical Cancer Research targeting the splicing factor NONO", in which the researchers uncovered a novel regulatory signaling axis that supports the progression of GBM. TRIM25 PROMOTES THE K63 chain ubiquitination of NONO and enhances the splicing efficiency. TRIM25 knockdown leads to the retention of a second intron in the pre-mRNA of PRMT1, hindering the production of mature PRMT1 mRNA, which in turn inhibits the activation of the c-MYC pathway in GBM cells. Targeting the E3 ligase activity of TRIM25 and disrupting the interaction of TRIM25 with NONO is a promising strategy for the treatment of GBM.
https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-02964-6
Background:
01
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite substantial advances in surgery, radiotherapy, and chemotherapy, the aggressive growth and relapse propensity of GBM remain its most prominent features, resulting in a median survival of 14 to 20 months. The infiltration of tumor cells into normal tissues is an important cause of poor prognosis of GBM. Over the past few years, many researchers have explored the biological changes in the pathogenesis of GBM, but further efforts are needed to identify effective therapeutic targets for GBM.
Among the various regulatory pathways in human cells, ubiquitination is the most prevalent (and possibly the most important) type of post-translational modification involved in the regulation of many diseases, including cancer. Ubiquitination typically forms bonds of one or more ubiquitin molecules at the lysine residue of the protein of interest. Depending on the type of polyubiquitin chain, ubiquitination can have unique functions: K48-chain ubiquitination promotes protein degradation by the 26S ubiquitin proteasome, while K63-chain ubiquitination regulates a variety of cellular processes (e.g., DNA repair, signaling, kinase activity, and endocytosis). Ubiquitination involves three enzymes, of which E3 ubiquitin ligase plays an important role in this process. As a result, they are thought to be implicated in the pathogenesis of many diseases and become potential therapeutic targets.
The study found
02
The researchers observed that TRIM25 was upregulated in GBM and was associated with enhanced growth and infiltration of glioblastoma cells, both in vitro and in vivo. Subsequently, the researchers screened a range of proteins that interacted with TRIM25, and mass spectrometry and co-immunoprecipitation revealed that NONO was a potential substrate for TRIM25. TRIM25 knockdown reduces K63-linker ubiquitination of NONO, thereby inhibiting the splicing function of NONO. Dysfunctional NONO leads to the retention of the pre-mRNA second intron of PRMT1, inhibiting the activation of the PRMT1/c-MYC pathway.
Findings:
03
Taken together, in this study, the researchers revealed a novel regulatory signaling axis that supports the progression of GBM. TRIM25 PROMOTES THE K63 chain ubiquitination of NONO and enhances the splicing efficiency. TRIM25 knockdown leads to the retention of a second intron in the pre-mRNA of PRMT1, hindering the production of mature PRMT1 mRNA, which in turn inhibits the activation of the c-MYC pathway in GBM cells. Targeting the E3 ligase activity of TRIM25 and disrupting the interaction of TRIM25 with NONO is a promising strategy for the treatment of GBM.
Resources:
https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-02964-6
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please visit a regular hospital.
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