Histone modifications silence the GATA transcription factor genes in ovarian cancer.
Altered expression of GATA factors was found and proposed as the underlying mechanism for dedifferentiation in ovarian carcinogenesis. In particular, GATA6 is lost or excluded from the nucleus in 85% of ovarian tumors and GATA4 expression is absent in majority of ovarian cancer cell lines. Here, we evaluated their DNA and histone epigenetic modifications in five ovarian epithelial and carcinoma cell lines (human 'immortalized' ovarian surface epithelium (HIO)-117, HIO-114, A2780, SKOV3 and ES2). GATA4 and GATA6 gene silencing was found to correlate with hypoacetylation of histones H3 and H4 and loss of histone H3/lysine K4 tri-methylation at their promoters in all lines. Conversely, histone H3/lysine K9 di-methylation and HP1gamma association were not observed, excluding reorganization of GATA genes into heterochromatic structures. The histone deacetylase inhibitor trichostatin A, but not the DNA methylation inhibitor 5'-aza-2'-deoxycytidine, re-established the expression of GATA4 and/or GATA6 in A2780 and HIO-114 cells, correlating with increased histone H3 and H4 acetylation, histone H3 lysine K4 methylation and DNase I sensitivity at the promoters. Therefore, altered histone modification of the promoter loci is one mechanism responsible for the silencing of GATA transcription factors and the subsequent loss of a target gene, the tumor suppressor Disabled-2, in ovarian carcinogenesis.
Caslini
C
C
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
Capo-chichi
C D
CD
Roland
I H
IH
Nicolas
E
E
Yeung
A T
AT
Xu
X-X
XX
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D002277:Carcinoma; D045744:Cell Line, Tumor; D005260:Female; D050980:GATA Transcription Factors / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000235:genetics; D050993:GATA6 Transcription Factor / Q000235:genetics; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006570:Heterochromatin / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine; D008745:Methylation; D010051:Ovarian Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D050980:GATA Transcription Factors; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D006570:Heterochromatin; D006657:Histones; D025521:Tumor Suppressor Proteins; D008239:Lysine