Estrogen down regulates COMT transcription via promoter DNA methylation in human breast cancer cells

Qian Wu, Shelly Odwin-Dacosta, Shuyuan Cao, James D Yager, Wan-Yee Tang

Research output: Contribution to journalArticlepeer-review

Abstract

Catechol-O-methyltransferase (COMT) acts as a ‘gate-keeper’ to prevent DNA damage during estrogen metabolism. Both experimental and epidemiological studies suggest the role of COMT in pathogenesis of human breast cancer (BCa). It was previously reported that inhibition of COMT enzyme activity in estradiol-treated human breast epithelial carcinoma-derived MCF-7 cells caused increased oxidative DNA damage and formation of mutagenic depurinating adducts. To improve our understanding of factors influencing estrogen metabolism in BCa, it requires a mechanistic study illustrating the regulation of this ‘gate-keeper’. We investigated the epigenetic mechanisms underlying decreased COMT transcription in MCF-7 cells exposed to 17ß-estradiol (E2) and the phytoestrogen, genistein (GEN). CpG site-specific methylation at promoters for both soluble (S) and membrane-bound (MB) COMT transcripts were assessed. Both E2 and GEN induced CpG site-specific methylation within the distal promoter of MB-COMT. In addition, ChIP analysis showed that there was increased binding of DNMT3B, MBD2 and HDAC1 within this promoter. These epigenetic changes were associated with decreased COMT transcript levels. Interestingly, sulforaphane, an antioxidant commonly found in cruciferous vegetables, was able to reverse the estrogen-induced epigenetic changes and gene silencing of COMT. Our data provide a new insight in epigenetically targeting COMT transcription. Since reactive estrogen metabolites may contribute to breast cancer, our findings may help in developing prevention and/or intervention strategies for human BCa.

Original languageEnglish (US)
Pages (from-to)12-22
Number of pages11
JournalToxicology and Applied Pharmacology
Volume367
DOIs
StatePublished - Mar 15 2019

Keywords

  • COMT
  • DNA Methylation
  • Epigenetics
  • Estradiol
  • Genistein
  • Sulforaphane

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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