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

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 G 0 /G 1 phase cell cycle arrest in bladder cancer cell.

A Network Pharmacology Approach to Investigate the Anticancer Mechanism and Potential Active Ingredients of Rheum palmatum L. Against Lung Cancer via Induction of Apoptosis

“…Epidermal growth factor receptor (EGFR) is a glycoprotein that plays an important role in physiological processes such as proliferation, apoptosis and differentiation of cell by activating the calcium signaling pathway, MAPK signaling pathway and PI3K/AKT signaling pathway ( Carlisle et al., 2007 ). As an important anticancer gene, the inactivation of p53 plays an important role in tumor formation, and increasing studies have found that the p53 plays a crucial role in retarding tumor cell cycle, promoting tumor cell apoptosis and inhibiting tumor angiogenesis ( Bi et al., 2018 ; Li P. et al., 2019 ; Wang et al., 2020 ).…”

Cross-Species Proteomics Identifies CAPG and SBP1 as Crucial Invasiveness Biomarkers in Rat and Human Malignant Mesothelioma

“…To give just a few more very recent examples of the protein’s importance, Lee et al have suggested that hepatitis B virus-X-expressing cells, which show markedly decreased SELENBP1 expression, might be one factor in the development of hepatocellular carcinoma caused by HBV infection [ 57 ]. Wang et al have also reported this protein’s novel function in transcriptionally modulating p21 expression through a p53-independent mechanism, with a resulting impact on the G 0 /G 1 phase cell cycle arrest in bladder cancer [ 58 ].…”

Differential expression and diagnostic significance of P53, MutS homologs 2, tropomyosin‐4 in alpha‐fetoprotein‐negative hepatocellular carcinoma

“…Recent studies have pointed out that abnormal expression of P53, MutS homologs 2 (MSH2), and tropomyosin-4 (Tm-4) was closely related to the occurrence and metastasis of various cancers. [4][5][6][7][8] P53 is considered to be an important tumor suppressor protein, but reports have pointed out that the P53 gene in many cancer cells will mutate and lose cellular gene repair function. 4 Wang et al 4 It is also well known that inflammation causes many cancers, especially liver cancer.…”

“…With the help of proteomics research technology, the pathogenesis of tumors can be further revealed at the protein level, and tumor‐specific markers and specific antigens can be screened and identified. Recent studies have pointed out that abnormal expression of P53, MutS homologs 2 (MSH2), and tropomyosin‐4 (Tm‐4) was closely related to the occurrence and metastasis of various cancers 4‐8 . P53 is considered to be an important tumor suppressor protein, but reports have pointed out that the P53 gene in many cancer cells will mutate and lose cellular gene repair function 4 .…”

“…P53 is considered to be an important tumor suppressor protein, but reports have pointed out that the P53 gene in many cancer cells will mutate and lose cellular gene repair function 4 . Wang et al 4 pointed out that P53 gene was significantly increased in bladder cancer tissues, and high expression of P53 protein was associated with poor prognosis in patients. Recently, researchers found that the oncogene long non‐coding RNA H19 can play a competitive endogenous ribonucleic acid to inhibit miR‐29 expression, thereby reducing the inhibitory function of miR‐29 on P53 gene expression and promoting the cancer metastasis 5 .…”