HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b

PLoS One. 2013 Dec 11;8(12):e83018. doi: 10.1371/journal.pone.0083018. eCollection 2013.

Abstract

Over the past years BARD1 (BRCA1-associated RING domain 1) has been considered as both a BRCA1 (BReast Cancer susceptibility gene 1, early onset) interactor and tumor suppressor gene mutated in breast and ovarian cancers. Despite its role as a stable heterodimer with BRCA1, increasing evidence indicates that BARD1 also has BRCA1-independent oncogenic functions. Here, we investigate BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s) and microRNAs. We show that the HDACi (histone deacetylase inhibitor) Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR-19b expression levels. Moreover, we identify a specific BARD1 isoform, which might act as tumor diagnostic and prognostic markers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Leukemic / drug effects*
  • HL-60 Cells
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Tumor Suppressor Proteins / biosynthesis*
  • Tumor Suppressor Proteins / genetics
  • U937 Cells
  • Ubiquitin-Protein Ligases / biosynthesis*
  • Ubiquitin-Protein Ligases / genetics
  • Vorinostat

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • MIRN19 microRNA, human
  • MicroRNAs
  • Protein Isoforms
  • RNA, Neoplasm
  • Tumor Suppressor Proteins
  • Vorinostat
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases

Grants and funding

Grant Support. This work was supported by EU: Blueprint (contract no. 282510); Italian IHEC (Flag Project: EPIGEN); the Italian Association for Cancer Research (AIRC no.11812); Italian Ministry of University and Research (PRIN_2009PX2T2E_004); PON0101227; Swiss National Research Foundations (NF 3100A0-122353), Ligue SuisseContre le Cancer (KLS 01962-10-2006), and LigueGenevoiseContre le Cancer (LGCC 1117) to IIF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.