Aspirin Mediates Its Antitumoral Effect Through Inhibiting PTTG1 in Pituitary Adenoma

J Clin Endocrinol Metab. 2022 Nov 23;107(11):3066-3079. doi: 10.1210/clinem/dgac496.

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.

Keywords: biomarker; demethylation; epigenetic; methylation; pitNET; pituitary; pituitary adenoma; pttg1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma* / drug therapy
  • Adenoma* / genetics
  • Aspirin / pharmacology
  • Decitabine
  • Humans
  • Mixed Function Oxygenases / metabolism
  • Pituitary Neoplasms* / drug therapy
  • Pituitary Neoplasms* / genetics
  • Pituitary Neoplasms* / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Aspirin
  • Decitabine
  • Mixed Function Oxygenases
  • Proto-Oncogene Proteins
  • TET1 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • UHRF2 protein, human
  • pituitary tumor-transforming protein 1, human