Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4

Cancer Med. 2018 Apr;7(4):1317-1325. doi: 10.1002/cam4.1324. Epub 2018 Feb 23.

Abstract

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring-between-Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5-Aza-2-deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl-CpG-binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

Keywords: Breast cancer; DNA methylation; MBD4; RNF144A; epigenetic regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Carrier Proteins / genetics*
  • CpG Islands
  • DNA Methylation*
  • Endodeoxyribonucleases / metabolism*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Humans
  • Middle Aged
  • Promoter Regions, Genetic*
  • Protein Binding
  • Ubiquitin-Protein Ligases / genetics*

Substances

  • Carrier Proteins
  • RNF144A protein, human
  • Ubiquitin-Protein Ligases
  • Endodeoxyribonucleases
  • MBD4 protein, human