阿司匹林
DNA去甲基化
转录组
DNA甲基化
细胞生长
基因表达
癸他滨
去甲基化
生物
癌症研究
药理学
化学
基因
生物化学
作者
Borbála Szabó,Kinga Németh,Katalin Mészáros,Lilla Krokker,István Likó,Éva Saskői,Krisztina Németh,Pál Szabó,Nikolette Szücs,Sándor Czirják,Gábor Szalóki,Attila Patócs,Henriett Butz
标识
DOI:10.1210/clinem/dgac496
摘要
Abstract Context DNA demethylation and inhibitory effects of aspirin on pituitary cell proliferation have been demonstrated. Objective Our aim was to clarify the molecular mechanisms behind the aspirin-related effects in pituitary cells. Methods DNA methylome and whole transcriptome profile were investigated in RC-4B/C and GH3 pituitary cell lines upon aspirin treatment. Effects of aspirin and a demethylation agent, decitabine, were further tested in vitro. PTTG1 expression in 41 human PitNET samples and whole genome gene and protein expression data of 76 PitNET and 34 control samples (available in Gene Expression Omnibus) were evaluated. Results Aspirin induced global DNA demethylation and consequential transcriptome changes. Overexpression of Tet enzymes and their cofactor Uhrf2 were identified behind the increase of 5-hydroxymethylcytosine (5hmC). Besides cell cycle, proliferation, and migration effects that were validated by functional experiments, aspirin increased Tp53 activity through p53 acetylation and decreased E2f1 activity. Among the p53 controlled genes, Pttg1 and its interacting partners were downregulated upon aspirin treatment by inhibiting Pttg1 promoter activity. 5hmC positively correlated with Tet1-3 and Tp53 expression, and negatively correlated with Pttg1 expression, which was reinforced by the effect of decitabine. Additionally, high overlap (20.15%) was found between aspirin-regulated genes and dysregulated genes in PitNET tissue samples. Conclusion A novel regulatory network has been revealed, in which aspirin regulated global demethylation, Tp53 activity, and Pttg1 expression along with decreased cell proliferation and migration. 5hmC, a novel tissue biomarker in PitNET, indicated aspirin antitumoral effect in vitro as well. Our findings suggest the potential beneficial effect of aspirin in PitNET.
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