The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases
The ubiquitous and tissue specific promoters of the human SRC gene are repressed by inhibitors of histone deacetylases
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DOI：
10.1038/sj.onc.1205787
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发表时间：
2002-09-12
期刊：
影响因子：
8
通讯作者：
Bonham, K
中科院分区：
文献类型：
--
作者：
Kostyniuk, CL;Dehm, SM;Bonham, K
组蛋白去乙酰化酶抑制剂作为潜在的化学预防剂和化学治疗剂引起了人们的浓厚兴趣，这是由于它们能够在不同的癌症衍生细胞系中诱导细胞周期停滞、分化和凋亡。60 kDa非受体酪氨酸激酶c-Src的激活在许多肿瘤和肿瘤衍生细胞系中是一致的发现，并且与这些相同的细胞过程有关。我们已经表明，组蛋白去乙酰化酶抑制剂，丁酸钠和曲古抑菌素A，抑制c-Src mRNA和蛋白质的表达，在结肠癌，乳腺癌和肝癌细胞系中的剂量依赖性的方式。我们的小组以前已经确定了两个不同的启动子，负责SRC转录，分开约1 kb的距离。丁酸钠和曲古抑菌素A强烈抑制这些高度不同的SRC启动子中的每一个的活性，证明组蛋白脱乙酰酶抑制剂直接抑制SRC转录。这种抑制不需要蛋白质新合成，也不与两种启动子活性所必需的蛋白质因子结合减少相关。我们发现丁酸钠和曲古抑菌素A抑制SRC启动子，这表明该癌基因可能是这些药物的主要靶点，并可能部分解释其抗癌活性。
Histone deacetylase inhibitors have generated keen interest as potential chemopreventive and chemotherapeutic agents due to their ability to induce cell cycle arrest, differentiation, and apoptosis in a diverse group of cancer derived cell lines. Activation of the 60 kDa nonreceptor tyrosine kinase, c-Src, has been a consistent finding in many tumors and tumor derived cell lines, and has been implicated in these same cellular processes. We have shown that the histone deacetylase inhibitors, sodium butyrate and Trichostatin A, repressed c-Src mRNA and protein expression in a dose-dependent manner in cell lines derived from cancers of the colon, breast;and liver. Our group has previously identified two distinct promoters that are responsible for SRC transcription, separated by a distance of approximately 1 kb. Sodium butyrate and Trichostatin A strongly inhibited activity of each of these highly disparate SRC promoters, demonstrating histone deacetylase inhibitors directly repress SRC transcription. This repression did not require protein neosynthesis and was not associated with a decrease in binding of protein factors essential for either promoter's activity. Our finding that sodium butyrate and Trichostatin A inhibit both SRC promoters suggest this oncogene may be a major target of these agents, and may explain in part their anti-cancer activity.