Loss of GATA6 leads to nuclear deformation and aneuploidy in ovarian cancer

Mol Cell Biol. 2009 Sep;29(17):4766-77. doi: 10.1128/MCB.00087-09. Epub 2009 Jul 6.

Abstract

A prominent hallmark of most human cancer is aneuploidy, which is a result of the chromosomal instability of cancer cells and is thought to contribute to the initiation and progression of most carcinomas. The developmentally regulated GATA6 transcription factor is commonly lost in ovarian cancer, and the loss of its expression is closely associated with neoplastic transformation of the ovarian surface epithelium. In the present study, we found that reduction of GATA6 expression with small interfering RNA (siRNA) in human ovarian surface epithelial cells resulted in deformation of the nuclear envelope, failure of cytokinesis, and formation of polyploid and aneuploid cells. We further discovered that loss of the nuclear envelope protein emerin may mediate the consequences of GATA6 suppression. The nuclear phenotypes were reproduced by direct suppression of emerin with siRNA. Thus, we conclude that diminished expression of GATA6 leads to a compromised nuclear envelope that is causal for polyploidy and aneuploidy in ovarian tumorigenesis. The loss of emerin may be the basis of nuclear morphological deformation and subsequently the cause of aneuploidy in ovarian cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aneuploidy*
  • Cell Nucleus / pathology*
  • Cell Nucleus / ultrastructure
  • Cell Transformation, Neoplastic / genetics
  • Chromosomal Instability
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology
  • Epithelial Cells / physiology
  • Female
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism*
  • Gene Silencing
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / pathology
  • Ovary / cytology
  • Phenotype
  • Polyploidy
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Tumor Cells, Cultured

Substances

  • GATA6 Transcription Factor
  • Histones
  • Membrane Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • emerin