NDLI: Selenium-binding protein 1 transcriptionally activates p21 expression via p53-independent mechanism and its frequent reduction associates with poor prognosis in bladder cancer

Content Provider	Springer Nature : BioMed Central
Author	Wang, Yulei Zhu, Wenzhen Chen, Xiaoqing Wei, Guangnan Jiang, Guosong Zhang, Guochun
Abstract	Background Recent studies have shown that selenium-binding protein 1 (SELENBP1) is significantly down-regulated in a variety of solid tumors. Nevertheless, the clinical relevance of SELENBP1 in human bladder cancer has not been described in any detail, and the molecular mechanism underlying its inhibitory role in cancer cell growth is largely unknown. Methods SELENBP1 expression levels in tumor tissues and adjacent normal tissues were evaluated using immunoblotting assay. The association of SELENBP1 expression, clinicopathological features, and clinical outcome was determined using publicly available dataset from The Cancer Genome Atlas bladder cancer (TCGA-BLCA) cohort. DNA methylation in SELENBP1 gene was assessed using online MEXPRESS tool. We generated stable SELENBP1-overexpression and their corresponding control cell lines to determine its potential effect on cell cycle and transcriptional activity of p21 by using flow cytometry and luciferase reporter assay, respectively. The dominant-negative mutant constructs, TAM67 and STAT1 Y701F, were employed to define the roles of c-Jun and STAT1 in the regulation of p21 protein. Results Here, we report that the reduction of SELENBP1 is a frequent event and significantly correlates with tumor progression as well as unfavorable prognosis in human bladder cancer. By utilizing TCGA-BLCA cohort, DNA hypermethylation, especially in gene body, is shown to be likely to account for the reduction of SELENBP1 expression. However, an apparent paradox is observed in its 3′-UTR region, in which DNA methylation is positively related to SELENBP1 expression. More importantly, we verify the growth inhibitory role for SELENBP1 in human bladder cancer, and further report a novel function for SELENBP1 in transcriptionally modulating p21 expression through a p53-independent mechanism. Instead, ectopic expression of SELENBP1 pronouncedly attenuates the phosphorylation of c-Jun and STAT1, both of which are indispensable for SELENBP1-mediated transcriptional induction of p21, thereby resulting in the G0/G1 phase cell cycle arrest in bladder cancer cell. Conclusions Taken together, our findings provide clinical and molecular insights into improved understanding of the tumor suppressive role for SELENBP1 in human bladder cancer, suggesting that SELENBP1 could potentially be utilized as a prognostic biomarker as well as a therapeutic target in future cancer therapy.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-020-02211-4.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-020-02211-4
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	18
Language	English
Publisher	BioMed Central
Publisher Date	2020-01-09
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Selenium-binding protein 1 (SELENBP1) p21 p53 c-Jun STAT1 Methylation Bladder cancer Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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