Chromobox Protein Homologue 7 Protein, with Decreased Expression in Human Carcinomas, Positively Regulates E-Cadherin Expression by Interacting with the Histone Deacetylase 2 Protein
Chromobox Protein Homologue 7 Protein, with Decreased Expression in Human Carcinomas, Positively Regulates E-Cadherin Expression by Interacting with the Histone Deacetylase 2 Protein
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DOI：
10.1158/0008-5472.can-09-1542
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Fusco, Alfredo
中科院分区：
文献类型：
--
作者：
Federico, Antonella;Pallante, Pierlorenzo;Fusco, Alfredo
染色质盒蛋白同源物7（CBX7）是一种编码新型多梳蛋白的染色质盒家族蛋白，其表达呈进行性降低，与甲状腺肿瘤的恶性程度密切相关。实际上，从良性腺瘤到乳头状、滤泡状和未分化甲状腺癌，CBX7蛋白水平降低的病例比例逐渐增加。为了阐明CBX7在肿瘤发生中的作用，我们通过蛋白质组学分析寻找与CBX7相互作用的蛋白。通过这种方法，我们鉴定出了几种蛋白。在这些蛋白中，我们选择了组蛋白去乙酰化酶2（HDAC2），众所周知，它在肿瘤细胞转化以及E - 钙黏蛋白表达下调中起关键作用，E - 钙黏蛋白的缺失是上皮 - 间质转化中的关键事件。我们通过免疫共沉淀证实CBX7与HDAC2蛋白发生物理相互作用，并能够抑制其活性。然后，我们发现这两种蛋白都结合E - 钙黏蛋白启动子，并且CBX7上调E - 钙黏蛋白的表达。与这些数据一致的是，我们发现人甲状腺癌中CBX7和E - 钙黏蛋白的表达呈正相关统计关系。最后，我们发现CBX7的表达增加了E - 钙黏蛋白启动子上组蛋白H3和H4的乙酰化状态。因此，CBX7通过与HDAC2相互作用并抑制其在E - 钙黏蛋白启动子上的活性来正向调节E - 钙黏蛋白表达的能力，可以解释CBX7表达缺失与高度恶性表型之间的相关性。[《癌症研究》2009年；69(17):7079 - 87]
Chromobox protein homologue 7 (CBX7) is a chromobox family protein encoding a novel polycomb protein, the expression of which shows a progressive reduction, well related with the malignant grade of the thyroid neoplasias. Indeed, CBX7 protein levels decreased in an increasing percentage of cases going from benign adenomas to papillary, follicular, and anaplastic thyroid carcinomas. To elucidate the function of CBX7 in carcinogenesis, we searched for CBX7 interacting proteins by a proteomic analysis. By this approach, we identified several proteins. Among these proteins, we selected histone deacetylase 2 (HDAC2), which is well known to play a key role in neoplastic cell transformation and down-regulation of E-cadherin expression, the loss of which is a critical event in the epithelial-to-mesenchymal transition. We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the F-cadherin promoter and that CBX7 up-regulates E-cadherin expression. Consistent with these data, we found a positive statistical correlation between CBX7 and E-cadherin expression in human thyroid carcinomas. Finally, we showed that the expression of CBX7 increases the acetylation status of the histones H3 and 114 on the E-cadherin promoter. Therefore, the ability of CBX7 to positively regulate E-cadherin expression by interacting with HDAC2 and inhibiting its activity on the E-cadherin promoter would account for the correlation between the loss of CBX7 expression and a highly malignant phenotype. [Cancer Res 2009;69(17):7079-87]