Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer

Oncogene. 2012 Feb 23;31(8):1034-44. doi: 10.1038/onc.2011.296. Epub 2011 Jul 18.

Abstract

The human POK family members are transcription factors with a POZ domain and zinc-fingers that act primarily as transcriptional repressors. Several members of this family are involved in oncogenesis and this prompted us to assess whether expression levels of individual POK family members are associated with clinical outcomes in cancer. We have observed that ZBTB4 (zinc-finger and BTB domain containing 4) is downregulated in breast cancer patients, and that its expression is significantly correlated with relapse-free survival. Further integrative analysis of mRNA and microRNA (miR) expression data from the NCI-60 cell lines revealed an inverse correlation between ZBTB4 and oncogenic miRs derived from the miR-17-92 cluster and its paralogs. The experimental results using MDA-MB-231 and MCF-7 human breast cancer cells confirm that miRNAs derived from these clusters, containing miR-17-5p, miR-20a, miR-106a, miR-106b and miR-93, negatively regulate ZBTB4 expression. Overexpression of ZBTB4 or restoration of ZBTB4 by using an antagomir inhibit growth and invasion of breast cancer cells, and this effect is due, in part, to ZBTB4-dependent repression of the specificity protein 1 (Sp1), Sp3 and Sp4 genes, and subsequent downregulation of several Sp-dependent oncogenes, in part, through competition between ZBTB4 and Sp transcription factors for GC-rich promoter sequences. These results confirm that ZBTB4 functions as a novel tumor-suppressor gene with prognostic significance for breast cancer survival, and the oncogenic miR-17-92/ZBTB4/Sp axis may be a potential therapeutic target.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease-Free Survival
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Humans
  • Kaplan-Meier Estimate
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Oncogenes*
  • Prognosis
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sp Transcription Factors / genetics
  • Sp Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • CCND1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • MIRN17-92 microRNA, human
  • MIRN20a microRNA, human
  • MicroRNAs
  • Repressor Proteins
  • Sp Transcription Factors
  • Tumor Suppressor Proteins
  • ZBTB4 protein, human
  • Cyclin D1
  • Luciferases