Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium

Katherine E. Pelch, Erik J. Tokar, B. Alex Merrick, Michael P. Waalkes

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10. μM Cd for 11. weeks (CTPE) or 5. μM iAs for 29. weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1) were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (>. 25-fold) and S100P (>. 40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (>. 15-fold) and NTM (>. 1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status.

Original languageEnglish
Pages (from-to)159-167
Number of pages9
JournalToxicology and Applied Pharmacology
Volume286
Issue number3
DOIs
StatePublished - 1 Aug 2015

Keywords

  • Cadmium
  • DNA methylation
  • Gene expression
  • Inorganic arsenic
  • Prostate cancer

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