JARID1B Expression and Its Function in DNA Damage Repair Are Tightly Regulated by miRNAs in Breast Cancer

Cancer Sci. 2019 Apr;110(4):1232-1243. doi: 10.1111/cas.13925. Epub 2019 Mar 18.

Abstract

JARID1B/KDM5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post-transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID1B upregulation, showed a strong downregulation of 2 microRNAs (miRNAs), mir-381 and mir-486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3'UTR and reduce luciferase's activity in a complementarity-driven repression assay. Moreover, MCF7 breast cancer cells overexpressing JARID1B showed a strong protein reduction when transfected with mir-486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, 3 features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNA's circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies.

Keywords: DNA damage; Ionizing radiation; KDM5 histone demethylase; breast cancer; microRNA.

MeSH terms

  • Biomarkers, Tumor
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • DNA Damage*
  • DNA Repair*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics*
  • MicroRNAs / genetics*
  • Nuclear Proteins / genetics*
  • RNA Interference
  • Radiation Tolerance / genetics
  • Repressor Proteins / genetics*
  • Reproducibility of Results
  • Transcriptome

Substances

  • Biomarkers, Tumor
  • MicroRNAs
  • Nuclear Proteins
  • Repressor Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5B protein, human