Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue

PLoS One. 2014 Aug 11;9(8):e104687. doi: 10.1371/journal.pone.0104687. eCollection 2014.

Abstract

Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Ontology
  • Gene Regulatory Networks / drug effects
  • Genome, Human / drug effects
  • Genome, Human / genetics
  • Genomics*
  • Humans
  • Ovarian Neoplasms / pathology*
  • Plicamycin / analogs & derivatives*
  • Plicamycin / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Sp1 Transcription Factor / metabolism
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects*

Substances

  • Antineoplastic Agents
  • Sp1 Transcription Factor
  • Transcription Factors
  • demycarosyl-3D-digitoxosylmithramycin SK
  • Plicamycin

Associated data

  • GEO/GSE46926

Grant support

This work was supported by grant BFU2010-15518 from the Spanish Ministry of Science and Innovation, and the FEDER program of the European Community, and it was performed within the framework of the “Xarxa de Referencia en Biotecnologia” of the Generalitat de Catalunya. Carolina Vizcaíno is recipient of a JAE-Predoc2010 fellowship (CSIC), co-financed by the European Social Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.