Estradiol-mediated inhibition of DNMT1 decreases p53 expression to induce M2-macrophage polarization in lung cancer progression

Yung Ching Chen, Ming Jer Young, Hui Ping Chang, Chia Yu Liu, Chia Chi Lee, Yau Lin Tseng, Yi Ching Wang, Wen Chang Chang, Jan Jong Hung

Research output: Contribution to journalArticlepeer-review

Abstract

Previous studies indicate that estrogen positively regulates lung cancer progression. Understanding the reasons will be beneficial for treating women with lung cancer in the future. In this study, we found that tumor formation was more significant in female EGFRL858R mice than in male mice. P53 expression levels were downregulated in the estradiol (E2)-treated lung cancer cells, female mice with EGFRL858R-induced lung cancer mice, and premenopausal women with lung cancer. E2 increased DNA methyltransferase 1 (DNMT1) expression to enhance methylation in the TP53 promoter, which led to the downregulation of p53. Overexpression of GFP-p53 decreased DNMT1 expression in lung cancer cells. TP53 knockout in mice with EGFRL858R-induced lung cancer not only changed gene expression in cancer cells but also increased the polarization of M2 macrophages by increasing C–C motif chemokine ligand 5 (CCL5) expression and decreasing growth differentiation factor 15 (GDF15) expression. The TP53 mutation rate was increased in females with late-stage but not early-stage lung cancer compared to males with lung cancer. In conclusion, E2-induced DNMT1 and p53 expression were negatively regulated each other in females with lung cancer, which not only affected cancer cells but also modulated the tumor-associated microenvironment, ultimately leading to a poor prognosis.

Original languageEnglish
Article number25
JournalOncogenesis
Volume11
Issue number1
DOIs
Publication statusPublished - 2022 Dec

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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