Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.
Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines.
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DOI：
10.1038/sj.bjc.6602984
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发表时间：
2006-03-27
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
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转录因子 2 基因 (TCF2) 编码肝细胞核因子 1β (HNF1β)，这是一种与发育和代谢相关的转录因子。在肾细胞癌中观察到 TCF2 突变，通过筛选异常甲基化基因，我们现已确定 TCF2 作为卵巢癌表观遗传失活的靶点。 TCF2 在 53% 的卵巢癌细胞系和 26% 的原发性卵巢癌中被甲基化，导致该基因表达缺失。用甲基转移酶抑制剂 5-aza-2' 脱氧胞苷 (5-aza-dC) 处理细胞可恢复 TCF2 表达。此外，染色质免疫沉淀显示甲基化细胞中组蛋白 H3 脱乙酰化，并且当与 5-aza-dC 结合时，组蛋白脱乙酰酶抑制剂曲古抑菌素 A 协同诱导 TCF2 表达。 TCF2 的表观遗传失活也出现在结直肠、胃和胰腺细胞系中，表明 TCF2 的表观遗传失活普遍参与肿瘤发生。 TCF2表达的恢复诱导HNF4α（HNF1β的转录靶标）的表达，表明TCF2的表观遗传沉默导致肿瘤中肝细胞核因子网络的改变。这些结果表明 TCF2 参与卵巢癌的发展，并可能代表其检测和治疗的有用靶标。
Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1β (HNF1β), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2′deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4α, a transcriptional target of HNF1β, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.
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DOI：
10.1073/pnas.0405776102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Haumaitre, C;Barbacci, E;Cereghini, S
通讯作者：
Cereghini, S
影响因子：
78.5
作者：
Issa, JP
通讯作者：
Issa, JP
影响因子：
39.2
作者：
Bellanné-Chantelot, C;Chauveau, D;Timsit, J
通讯作者：
Timsit, J
影响因子：
30.8
作者：
Bluteau, O;Jeannot, E;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
64.5
作者：
CEREGHINI, S;RAYMONDJEAN, M;YANIV, M
通讯作者：
YANIV, M