PRDM1 promotes the ferroptosis and immune escape of thyroid cancer by regulating USP15-mediated SELENBP1 deubiquitination

• Published in: Journal of endocrinological investigation Vol. 47; no. 12; pp. 2981 - 2997
• Main Authors: Ma, J., Li, Z., Xu, J., Lai, J., Zhao, J., Ma, L., Sun, X.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2024; Springer Nature B.V
• Subjects: Animals; CD11b antigen; Cell growth; Cell Line, Tumor; Cell migration; Cell Proliferation; Chromatin; CXCL10 protein; Endocrinology; Female; Ferroptosis; Ferroptosis - physiology; Flow cytometry; Gene Expression Regulation, Neoplastic; Granzyme B; Humans; Immune evasion; Immunoprecipitation; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Nude; Middle Aged; Monocyte chemoattractant protein 1; Original Article; Positive Regulatory Domain I-Binding Factor 1 - genetics; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Proteins; Selenium; Selenium-Binding Proteins - genetics; Selenium-Binding Proteins - metabolism; Therapeutic targets; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid Neoplasms - immunology; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transforming growth factor-b1; Tumor Escape; Tumor necrosis factor-α; Tumors; Ubiquitin; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism; Ubiquitination; Zinc finger proteins; SELENBP1; Ferroptosis; USP15; Thyroid cancer; PRDM1; Immune escape
• ISSN: 1720-8386; 0391-4097; 1720-8386
• DOI: 10.1007/s40618-024-02385-4

Background The deubiquitinating enzyme Ubiquitin-specific peptidase 15 (USP15) is upregulated in various cancers and promotes tumor progression by increasing the expression of several oncogenes. This project is designed to explore the role and mechanism of USP15 in thyroid cancer (TC) progression. Methods Selenium-binding protein 1 (SELENBP1), USP15, CCL2/5, CXCL10/11, IL-4, and TGF-β1 mRNA levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). SELENBP1, USP15, GPX4, IL-10, Arg-1, Granzyme B, TNF-α, and PR domain zinc finger protein 1 (PRDM1) protein levels were examined by western blot assay. Fe + level, malondialdehyde (MDA), and lipid-ROS levels were determined using special kits. The proportion of CD11b + CD206 + positive cells was detected using a flow cytometry assay. The role of SELENBP1 on TC cell growth was examined using a xenograft tumor model in vivo . After GeneMANIA prediction, the interaction between USP15 and SELENBP1 was verified using Co-immunoprecipitation (CoIP) assay. The binding between PRDM1 and USP15 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Results SELENBP1 was increased in TC subjects and cell lines, and its knockdown repressed TC cell proliferation, migration, invasion, immune escape, and induced ferroptosis in vitro, as well as blocked tumor growth in vivo. In mechanism, USP15 interacted with SELENBP1 and maintained its stabilization by removing ubiquitin. Meanwhile, the upregulation of USP15 was induced by the transcription factor PRDM1. Conclusion USP15 transcriptionally mediated by PRDM1 might boost TC cell malignant behaviors through deubiquitinating SELENBP1, providing a promising therapeutic target for TC treatment.