Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK
Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK
复制标题
DOI：
10.1016/j.cellsig.2003.11.001
复制
发表时间：
2004-06-01
影响因子：
4.8
通讯作者：
Hung, WC
中科院分区：
文献类型：
--
作者：
Chang, HC;Liu, LT;Hung, WC
RECK 是一种膜锚定糖蛋白，可能负向调节基质金属蛋白酶 (NIMP) 活性并抑制肿瘤转移。先前的研究表明，致癌性 ras 通过 RECK 启动子中的 Sp1 结合位点抑制 RECK 表达。在本研究中，我们研究了ras抑制RECK表达的分子机制。共转染实验表明，Sp1 和 Sp3 是 RECK 基因的反式激活子，而不是阻遏子。因此，我们测试了 ras 激活是否诱导组蛋白脱乙酰酶 (HDAC) 与 Sp1 结合以抑制 RECK 表达。我们的数据显示，在 ras 诱导后，细胞中与 Sp1 相关的 HDAC1 增加。通过使用 DNA 亲和沉淀测定，我们发现致癌 ras 的诱导增强了 HDAC1 与 RECK 启动子中 Sp1 位点对应的 DNA 探针的结合。此外，HDAC 抑制剂曲古抑菌素 A (TSA) 可有效拮抗 ras 对 RECK 的抑制作用。还讨论了 ras 抑制 RECK 的信号通路。在 2-12 细胞中，致癌 ras 的诱导会激活细胞外信号调节激酶 (ERK)，但不会激活 c-Jun N 末端激酶 (JNK) 和 p38(HOG) 激酶。添加 PD98059 或过表达 ERK2 显性失活突变体确实逆转了 ras 介导的 RECK 启动子活性抑制。综上所述，我们的结果表明致癌 ras 通过历史性的脱乙酰化机制抑制 RECK 表达。 (C) 2003 Elsevier Inc. 保留所有权利。
RECK is a membrane-anchored glycoprotein that may negatively regulate matrix metalloproteinase (NIMP) activity and inhibit tumor metastasis. Previous study demonstrated that oncogenic ras inhibited RECK expression via an Sp1 binding site in the RECK promoter. In this study, we investigated the molecular mechanism by which ras inhibited RECK expression. Co-transfection assay showed that Sp1 and Sp3 are transactivators, rather than repressors, for RECK gene. So, we tested whether ras activation induced the binding of histone deacetylases (HDACs) to Sp1 to repress RECK expression. Our data showed Sp1-associated HDAC1 in cells was increased after ras induction. By using DNA affinity precipitation assay, we found that induction of oncogenic ras enhanced the binding of HDAC1 to the DNA probe corresponding to the Sp1 site in the RECK promoter. Additionally, a HDAC inhibitor trichostatin A (TSA) potently antagonized the inhibitory action of ras on RECK. The signaling pathway by which ras suppresses RECK was also addressed. Induction of oncogenic ras activated extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38(HOG) kinase in 2-12 cells. Addition of PD98059 or overexpression of dominant-negative mutant of ERK2 indeed reversed ras-mediated inhibition of RECK promoter activity. Taken together, our results suggest that oncogenic ras represses RECK expression via a historic deacetylation mechanism. (C) 2003 Elsevier Inc. All rights reserved.