Involvement of DNA hypermethylation in down-regulation of the zinc transporter ZIP8 in cadmium-resistant metallothionein-null cells

Hitomi Fujishiro, Satomi Okugaki, Saori Yasumitsu, Shuichi Enomoto, Seiichiro Himeno

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The Zrt/Irt-related protein 8 (ZIP8) encoded by slc39a8 is now emerging as an important zinc transporter involved in cellular cadmium incorporation. We have previously shown that mRNA and protein levels of ZIP8 were decreased in cadmium-resistant metallothionein-null (A7) cells, leading to a decrease in cadmium accumulation. However, the mechanism by which ZIP8 expression is suppressed in these cells remains to be elucidated. In the present study, we investigated the possibility that epigenetic silencing of the slc39a8 gene by DNA hypermethylation is involved in the down-regulation of ZIP8 expression. A7 cells showed a higher mRNA level of DNA methyltransferase 3b than parental cells. Hypermethylation of the CpG island of the slc39a8 gene was detected in A7 cells. Treatment of A7 cells with 5-aza-deoxycytidine, an inhibitor of DNA methyltransferase, caused demethylation of the CpG island of the slc39a8 gene and enhancement of mRNA and protein levels of ZIP8. In response to the recovery of ZIP8 expression, A7 cells treated with 5-aza-deoxycytidine showed an increase in cadmium accumulation and consequently an increase in sensitivity to cadmium. These results suggest that epigenetic silencing of the slc39a8 gene by DNA hypermethylation plays an important role in the down-regulation of ZIP8 in cadmium-resistant metallothionein-null cells.

Original languageEnglish
Pages (from-to)195-201
Number of pages7
JournalToxicology and Applied Pharmacology
Volume241
Issue number2
DOIs
Publication statusPublished - Dec 1 2009
Externally publishedYes

Keywords

  • Cadmium
  • DNA hypermethylation
  • Epigenetics
  • Resistance
  • Transport
  • Zinc

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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