SETBP1 activation upon MDM4-enhanced ubiquitination of NR3C1 triggers dissemination of colorectal cancer cells.

Autor: Zhai P; Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Gusu District, Suzhou, 215004, Jiangsu, People's Republic of China.; Department of General Surgery, Fifth People's Hospital of Huai'an City, Huai'an, 223300, Jiangsu, People's Republic of China., Zhang H; Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, 211200, Jiangsu, People's Republic of China., Li Q; Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Gusu District, Suzhou, 215004, Jiangsu, People's Republic of China.; Department of Gerneral Surgery, The Second Afilliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, People's Republic of China., Hu Z; Department of General Surgery, Fifth People's Hospital of Huai'an City, Huai'an, 223300, Jiangsu, People's Republic of China., Zhang H; Department of General Surgery, Fifth People's Hospital of Huai'an City, Huai'an, 223300, Jiangsu, People's Republic of China., Yang M; Department of General Surgery, Fifth People's Hospital of Huai'an City, Huai'an, 223300, Jiangsu, People's Republic of China., Xing C; Department of General Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Gusu District, Suzhou, 215004, Jiangsu, People's Republic of China. xingcg@suda.edu.cn., Guo Y; Department of General Surgery, Fifth People's Hospital of Huai'an City, Huai'an, 223300, Jiangsu, People's Republic of China. hawy_gyh@163.com.
Jazyk: angličtina
Zdroj: Clinical & experimental metastasis [Clin Exp Metastasis] 2024 Oct; Vol. 41 (5), pp. 747-764. Date of Electronic Publication: 2024 May 26.
DOI: 10.1007/s10585-024-10294-2
Abstrakt: Colorectal cancer (CRC) presents a growing concern globally, marked by its escalating incidence and mortality rates, thus imposing a substantial health burden. This investigation delves into the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in CRC metastasis and explores the associated mechanism. Through a comprehensive bioinformatics analysis, NR3C1 emerged as a gene with diminished expression levels in CRC. This finding was corroborated by observations of a low-expression pattern of NR3C1 in both CRC tissues and cells. Furthermore, experiments involving NR3C1 knockdown revealed an exacerbation of proliferation, migration, and invasion of CRC cells in vitro. Subsequent assessments in mouse xenograft tumor models, established by injecting human HCT116 cells either through the tail vein or at the cecum termini, demonstrated a reduction in tumor metastasis to the lung and liver, respectively, upon NR3C1 knockdown. Functionally, NR3C1 (glucocorticoid receptor) suppressed SET binding protein 1 (SETBP1) transcription by binding to its promoter region. Notably, mouse double minute 4 (MDM4) was identified as an upstream regulator of NR3C1, orchestrating its downregulation via ubiquitination-dependent proteasomal degradation. Further investigations unveiled that SETBP1 knockdown suppressed migration and invasion, and epithelial to mesenchymal transition of CRC cells, consequently impeding in vivo metastasis in murine models. Conversely, upregulation of MDM4 exacerbated the metastatic phenotype of CRC cells, a propensity mitigated upon additional upregulation of NR3C1. In summary, this study elucidates a cascade wherein MDM4-mediated ubiquitination of NR3C1 enables the transcriptional activation of SETBP1, thereby propelling the dissemination of CRC cells.
(© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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