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Identification of epigenetically silenced genes in tumor endothelial cells

(2007) CANCER RESEARCH. 67(9). p.4138-4148
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Abstract
Tumor angiogenesis requires intricate regulation of gene expression in endothelial cells. We recently showed that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors directly repress endothelial cell growth and tumor angiogenesis, suggesting that epigenetic modifications mediated by DNMTs and HDAC are involved in regulation of endothelial cell gene expression during tumor angiogenesis. To understand the mechanisms behind the epigenetic regulation of tumor angiogenesis, we used microarray analysis to perform a comprehensive screen to identify genes down- regulated in tumor-conditioned versus quiescent endothelial cells, and reexpressed by 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA). Among the 81 genes identified, 77% harbored a promoter CpG island. Validation of mRNA levels of a subset of genes confirmed significant down-regulation in tumor-conditioned endothelial cells and reactivation by treatment with a combination of DAC and TSA, as well as by both compounds separately. Silencing of these genes in tumor-conditioned endothelial cells correlated with promoter histone H3 deacetylation and loss of H3 lysine 4 methylation, but did not involve DNA methylation of promoter CpG islands. For six genes, down-regulation in microdissected human tumor endothelium was confirmed. Functional validation by RNA interference revealed that clusterin, fibrillin 1, and quiescin Q6 are negative regulators of endothelial cell growth and angiogenesis. In summary, our data identify novel angiogenesis-suppressing genes that become silenced in tumor-conditioned endothelial cells in association with promoter histone modifications and reactivated by DNMT and HDAC inhibitors through reversal of these epigenetic modifications, providing a mechanism for epigenetic regulation of tumor angiogenesis.
Keywords
FACTOR-BINDING PROTEIN-3, HISTONE DEACETYLASE INHIBITION, NITRIC-OXIDE SYNTHASE, DNA-METHYLATION, PROMOTER HYPERMETHYLATION, SUPPRESSOR GENES, CPG ISLANDS, ANGIOGENESIS, EXPRESSION, GROWTH

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Citation

Please use this url to cite or link to this publication:

Chicago
Hellebrekers, Debby MEI, Veerle Melotte, Emmanuelle Viré, Elise Langenkamp, Grietje Molema, François Fuks, James G Herman, Wim Van Criekinge, Arjan W Griffioen, and Manon Van Engeland. 2007. “Identification of Epigenetically Silenced Genes in Tumor Endothelial Cells.” Cancer Research 67 (9): 4138–4148.
APA
Hellebrekers, D. M., Melotte, V., Viré, E., Langenkamp, E., Molema, G., Fuks, F., Herman, J. G., et al. (2007). Identification of epigenetically silenced genes in tumor endothelial cells. CANCER RESEARCH, 67(9), 4138–4148.
Vancouver
1.
Hellebrekers DM, Melotte V, Viré E, Langenkamp E, Molema G, Fuks F, et al. Identification of epigenetically silenced genes in tumor endothelial cells. CANCER RESEARCH. 2007;67(9):4138–48.
MLA
Hellebrekers, Debby MEI, Veerle Melotte, Emmanuelle Viré, et al. “Identification of Epigenetically Silenced Genes in Tumor Endothelial Cells.” CANCER RESEARCH 67.9 (2007): 4138–4148. Print.
@article{791293,
  abstract     = {Tumor angiogenesis requires intricate regulation of gene expression in endothelial cells. We recently showed that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors directly repress endothelial cell growth and tumor angiogenesis, suggesting that epigenetic modifications mediated by DNMTs and HDAC are involved in regulation of endothelial cell gene expression during tumor angiogenesis. To understand the mechanisms behind the epigenetic regulation of tumor angiogenesis, we used microarray analysis to perform a comprehensive screen to identify genes down- regulated in tumor-conditioned versus quiescent endothelial cells, and reexpressed by 5-aza-2'-deoxycytidine (DAC) and trichostatin A (TSA). Among the 81 genes identified, 77\% harbored a promoter CpG island. Validation of mRNA levels of a subset of genes confirmed significant down-regulation in tumor-conditioned endothelial cells and reactivation by treatment with a combination of DAC and TSA, as well as by both compounds separately. Silencing of these genes in tumor-conditioned endothelial cells correlated with promoter histone H3 deacetylation and loss of H3 lysine 4 methylation, but did not involve DNA methylation of promoter CpG islands. For six genes, down-regulation in microdissected human tumor endothelium was confirmed. Functional validation by RNA interference revealed that clusterin, fibrillin 1, and quiescin Q6 are negative regulators of endothelial cell growth and angiogenesis. In summary, our data identify novel angiogenesis-suppressing genes that become silenced in tumor-conditioned endothelial cells in association with promoter histone modifications and reactivated by DNMT and HDAC inhibitors through reversal of these epigenetic modifications, providing a mechanism for epigenetic regulation of tumor angiogenesis.},
  author       = {Hellebrekers, Debby MEI and Melotte, Veerle and Vir{\'e}, Emmanuelle and Langenkamp, Elise and Molema, Grietje and Fuks, Fran\c{c}ois and Herman, James G and Van Criekinge, Wim and Griffioen, Arjan W and Van Engeland, Manon},
  issn         = {0008-5472},
  journal      = {CANCER RESEARCH},
  language     = {eng},
  number       = {9},
  pages        = {4138--4148},
  title        = {Identification of epigenetically silenced genes in tumor endothelial cells},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-06-3032},
  volume       = {67},
  year         = {2007},
}

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