Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway

Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC).In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status.

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“…Xu et al . (2014) suggested that inhibition of HATs may lead to p53 deacetylation, resulting in the transactivation of p53‐regulated genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of urinary bladder cancer cell proliferation by silibinin

Barros

Lima

Almeida

et al. 2020

Environ and Mol Mutagen

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“…Studies have shown that molecular target pathways, such as the growth factor pathway, Ras pathway, PI3K pathway, p53 pathway, and tumor metastasis invasion pathway, have great potential for the development of meaningful treatment strategies for glioma [33,34]. The p53 pathway is one of the important pathways for the molecular pathogenesis of glioma.…”

Section: Discussionmentioning

confidence: 99%

Joint bioinformatics analysis of underlying potential functions of hsa-let-7b-5p and core genes in human glioma

Chu

Liu

et al. 2019

J Transl Med

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Background: Glioma accounts for a large proportion of cancer, and an effective treatment for this disease is still lacking because of the absence of specific driver molecules. Current challenges in the treatment of glioma are the accurate and timely diagnosis of brain glioma and targeted treatment plans. To investigate the diagnostic biomarkers and prospective role of miRNAs in the tumorigenesis and progression of glioma, we analyzed the expression of miRNAs and key genes in glioma based on The Cancer Genome Atlas database. Methods: Of the 701 cases that were downloaded, five were normal and 696 were glioma. Then, 1626 differentially expressed genes were identified, and 173 aberrantly expressed miRNAs were calculated by edgeR. GO and KEGG pathway enrichment analyses were performed using Cytoscape software. A coexpression network was built by weighted correlation network analysis (WGCNA). A cell scratch test and transwell, cell apoptosis and cell cycle assays were performed to validate the function of hsa-let-7b-5p. Results: Based on crosstalk genes in the KEGG, PPI network, and WGCNA analyses, PLK1, CCNA2, cyclin B2 (CCNB2), and AURKA were screened as candidate diagnostic marker genes. The survival analysis revealed that high mRNA expression of PLK1, CCNA2, and AURKA was significantly associated with poor overall survival. Furthermore, hsalet-7b-5p was identified as a core miRNA in the regulation of candidate genes involved in glioma development. We confirmed that hsa-let-7b-5p could inhibit the migration, invasion, and cell cycle of glioma cells. Conclusions: This study provides four potential biomarkers for the diagnosis of glioma, offers a potential explanation of its pathogenesis, and proposes hsa-let-7b-5p as a therapeutic target.

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“…Despite the advances in surgical resection, chemotherapy and radiotherapy, the prognosis of patients with glioma remains poor, resulting in an overall 5-year survival rate of <10%. Currently, glioma ranks third worldwide as the cause of cancer-associated mortality, after pancreatic cancer and lung cancer (2). The standard therapy for newly diagnosed glioma is surgical resection followed by adjuvant radiotherapy and/or chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

A study on the correlation between STAT‑1 and mutant p53 expression in glioma

Yang

Wang

et al. 2018

Mol Med Report

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Glioma is the most common primary brain tumor in adults and the second most common malignant tumor in children. Aberrant expression of signal transducer and activator of transcription 1 (STAT‑1) and p53 are known to affect the occurrence and progression of malignant tumors. The aim of the present study was to investigate the expression of STAT‑1 and mutant p53 gene, as well as their correlation, in patients with glioma. The present study included 50 patients who underwent glioma resection at the First Affiliated Hospital of Inner Mongolia Medical University between December 2007 and December 2011, and 10 patients with acute cerebral contusion who underwent intracerebral hematoma removal at the same hospital between January 2013 and January 2014. The expression of STAT‑1 and mutant p53 protein in patients with different grades of glioma was assessed by immunohistochemistry. Spearman's correlation coefficient was employed to examine the correlation between STAT‑1 and the grade of glioma, and mutant p53 expression. The results demonstrated that the mean expression of STAT‑1 in glioma was significantly lower compared with normal brain tissue (P<0.05). However, there was no significant difference in the STAT‑1 positive expression rate between the two groups (χ2=1.38, P>0.05). The expression score (P<0.05) and positive expression rate (χ2=31.27, P<0.05) of mutant p53 in glioma was significantly higher compared with those in normal brain tissue. Statistical analysis revealed a negative correlation between STAT‑1 expression and the grade of glioma (r=‑0.767, P<0.05). In addition, mutant p53 expression was negatively correlated with STAT‑1 expression in glioma (r=‑0.876, P<0.05). The observed negative correlation between STAT‑1 and the pathological grade of glioma suggested an association between STAT‑1 and the occurrence and development of glioma, thus revealing the potential of STAT‑1 as a diagnostic biomarker and therapeutic target for glioma.

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Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway

Cited by 22 publications

References 39 publications

Inhibition of urinary bladder cancer cell proliferation by silibinin

Inhibition of urinary bladder cancer cell proliferation by silibinin

Joint bioinformatics analysis of underlying potential functions of hsa-let-7b-5p and core genes in human glioma

A study on the correlation between STAT‑1 and mutant p53 expression in glioma

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