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Histone modifications silence the GATA transcription factor genes in ovarian cancer

C Caslini1, C D Capo-chichi, I H Roland

  • 1Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.

Oncogene
|April 12, 2006
PubMed

Insights

Altered histone modifications silence GATA4 and GATA6 genes in ovarian cancer, leading to loss of the tumor suppressor Disabled-2. This epigenetic silencing is a key mechanism in ovarian carcinogenesis.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Oncology

Background:

  • GATA factors (GATA4, GATA6) are crucial in development and their altered expression is linked to ovarian carcinogenesis.
  • Loss or exclusion of GATA6 from the nucleus occurs in 85% of ovarian tumors, with GATA4 absent in most ovarian cancer cell lines.

Purpose of the Study:

  • To investigate DNA and histone epigenetic modifications of GATA4 and GATA6 in ovarian epithelial and carcinoma cell lines.
  • To determine the role of epigenetic alterations in the silencing of GATA factors during ovarian carcinogenesis.

Main Methods:

  • Analysis of DNA and histone epigenetic modifications (acetylation, methylation) at GATA4 and GATA6 promoters in five ovarian cell lines.
  • Treatment with histone deacetylase inhibitor (trichostatin A) and DNA methylation inhibitor (5'-aza-2'-deoxycytidine) to assess gene re-expression.
  • Assessing promoter sensitivity to DNase I digestion.

Main Results:

  • GATA4 and GATA6 gene silencing correlated with hypoacetylation of histones H3/H4 and reduced H3K4 tri-methylation at their promoters.
  • No evidence of heterochromatic reorganization (H3K9 di-methylation, HP1gamma association) was found.
  • Trichostatin A, but not 5'-aza-2'-deoxycytidine, restored GATA4/GATA6 expression, accompanied by increased histone acetylation, H3K4 methylation, and promoter DNase I sensitivity.

Conclusions:

  • Altered histone modifications at promoter loci are a significant mechanism for GATA transcription factor silencing in ovarian carcinogenesis.
  • This silencing contributes to the loss of the tumor suppressor Disabled-2, promoting ovarian cancer development.

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