Abstract
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 HP1γ 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.
| Original language | English |
|---|---|
| Pages (from-to) | 5446-5461 |
| Number of pages | 16 |
| Journal | Oncogene |
| Volume | 25 |
| Issue number | 39 |
| DOIs | |
| State | Published - Aug 31 2006 |
| Externally published | Yes |
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Keywords
- Chromatin
- Disabled-2 (DAB2)
- GATA transcription factors
- Ovarian carcinomas
- Ovarian epithelial cells
- Transcription repression
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Histone modifications silence the GATA transcription factor genes in ovarian cancer. / Caslini, C.; Capo-Chichi, C. D.; Roland, I. H.; Nicolas, E.; Yeung, A. T.; Xu, Xiangxi.
In: Oncogene, Vol. 25, No. 39, 31.08.2006, p. 5446-5461.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone modifications silence the GATA transcription factor genes in ovarian cancer
AU - Caslini, C.
AU - Capo-Chichi, C. D.
AU - Roland, I. H.
AU - Nicolas, E.
AU - Yeung, A. T.
AU - Xu, Xiangxi
PY - 2006/8/31
Y1 - 2006/8/31
N2 - 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 HP1γ 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.
AB - 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 HP1γ 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.
KW - Chromatin
KW - Disabled-2 (DAB2)
KW - GATA transcription factors
KW - Ovarian carcinomas
KW - Ovarian epithelial cells
KW - Transcription repression
UR - http://www.scopus.com/inward/record.url?scp=33748297582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748297582&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1209533
DO - 10.1038/sj.onc.1209533
M3 - Article
C2 - 16607277
AN - SCOPUS:33748297582
VL - 25
SP - 5446
EP - 5461
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 39
ER -