Xujun Li, Jing Jiang, Qian Wu, Tianzi You, Fan Yang
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引用次数: 0
Abstract
TRIM58 is a member of the TRIM protein family, which possess with E3 ubiquitin ligase activities. Studies have revealed that low expression of TRIM58 plays key roles, has been implicated in the tumor progression of tumor formation due to its reduced expression. However, its role in regulating the stemness of breast cancer stem cells (CSCs) remains unexplored. Here, we found that TRIM58 was underexpressed in TNBC tissues and cells compared to adjacent mucosa tissue, and its downregulation was significantly associated with shorter survival. Overexpression of TRIM58 reduced the proportion of CD44 + /CD24- cells, upregulated differentiation genes, and inhibited stemness-related gene expression in TNBC CSCs. In vitro and in vivo experiments revealed that TRIM58 overexpression in CSCs suppressed tumor sphere formation and tumorigenic capacity. Co-IP results indicated direct interaction between TRIM58 and MYH9, with TRIM58 inducing MYH9 degradation via ubiquitination in differentiated cells. Label-free quantitative proteomics identified GRK3 and Hippo-YAP as downstream targets and signaling pathways of MYH9. TIMER database analysis, immunohistochemistry, western blotting, DNA-protein pulldown experiments, and dual luciferase reporter assays demonstrated that MYH9 regulated GRK3 transcriptional activation in CSCs. In conclusion, elevated TRIM58 expression in CSCs downregulates MYH9 protein levels by promoting ubiquitin-mediated degradation, thereby inhibiting downstream GRK3 transcription, inactivating the YAP stemness pathway, and ultimately promoting CSC differentiation.
期刊介绍:
Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair.
Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.