DNA demethylation and inhibitory effect of Aspirin on pituitary cell proliferation
have been demonstrated.was to clarify the molecular mechanisms behind the Aspirin-related
effects in pituitary cells.DNA methylome and whole transcriptome profile were investigated
in RC4-B/C and GH3 pituitary cell lines upon Aspirin treatment. Effects of Aspirin
and 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.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 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, Tp53 expression, and negatively correlated with
Pttg1 expression that 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.A novel regulatory network has been revealed, where 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 too. Our findings suggest the potential beneficial
effect of Aspirin in PitNET.
