Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.
Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.
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DOI：
10.1530/erc-10-0320
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发表时间：
2011-06
影响因子：
3.9
通讯作者：
Meinkoth JL
中科院分区：
文献类型：
--
作者：
Dong X;Korch C;Meinkoth JL
Rap活性的增加与肿瘤进展相关。尽管Rap中的激活突变尚未被描述，但Rap 1GAP的下调在包括甲状腺癌在内的人类肿瘤中是常见的。在这项研究中，我们探讨了内源性Rap 1GAP表达是否可以恢复甲状腺肿瘤细胞。脱乙酰酶抑制剂和去甲基化剂，单独和组合的影响，在四个分化和6间变性甲状腺癌（ATC）细胞系进行了检查。结构不同的组蛋白脱乙酰酶（HDAC）抑制剂，丁酸钠和阿司他丁A，治疗增加Rap 1GAP表达在所有分化的甲状腺癌细胞系和六个ATC细胞系中的四个。去甲基化剂，5-氮杂-脱氧胞苷，恢复Rap 1GAP的表达在一个间变性细胞系和增强HDAC抑制剂在第二间变性细胞系的影响。Western blotting结果显示Rap 2在人甲状腺癌细胞中高表达。重要的是，HDAC抑制剂治疗损害分化和间变性肿瘤细胞系中的Rap 2活性。Rap活性被抑制的机制似乎需要对多种Rap调节因子（包括RapGEF和RapGAP）的表达产生影响。这些结果表明，HDAC抑制剂可以提供一种易于处理的方法来损害人类肿瘤细胞中的Rap活性。
Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines. Treatment with the structurally distinct histone deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A, increased Rap1GAP expression in all the differentiated thyroid carcinoma cell lines and in four of the six ATC cell lines. The demethylating agent, 5-aza-deoxycytidine, restored Rap1GAP expression in one anaplastic cell line and enhanced the effects of HDAC inhibitors in a second anaplastic cell line. Western blotting indicated that Rap2 was highly expressed in human thyroid cancer cells. Importantly, treatment with HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic tumor cell lines. The mechanism through which Rap activity is repressed appears to entail effects on the expression of multiple Rap regulators, including RapGEFs and RapGAPs. These results suggest that HDAC inhibitors may provide a tractable approach to impair Rap activity in human tumor cells.