HDAC3 in COLON CANCER

HDAC3 在结肠癌中的作用

基本信息

批准号：
7667934
负责人：
John M Mariadason
金额：
$ 19.97万
依托单位：
LUDWIG INSTITUTE FOR CANCER RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667934
关键词：
Address Alkaline Phosphatase Apoptosis Butyrates Cell Cycle Arrest Cell Differentiation Inhibition Cell Differentiation process Cell Maturation Cell Proliferation Cells Colon Colon Carcinoma Colorectal Complex Epithelial Cells Family Gene Expression Profiling Genes HDAC3 gene Histone Deacetylase Histone Deacetylase Inhibitor Human In Vitro Inhibition of Cell Proliferation Intestinal Mucosa Intestines Length Maintenance Malignant Neoplasms Mediating Molecular Mus Pattern Physiological Play Repression Repressor Proteins Research Design Role Signal Pathway Signal Transduction Small Intestines Small intestine mucous membrane Sodium Butyrate Testing Transgenic Mice Villus Volatile Fatty Acids cancer cell cancer therapy gene repression genome wide association study in vivo insight interest member overexpression programs promoter response tumor tumorigenesis villin

项目摘要

DESCRIPTION (provided by applicant): The histone deacetylase (HDAC) family of transcriptional co-repressors, currently comprising 18 members, are emerging as important regulators of colon cell maturation and transformation. For example, inhibitors of HDAC activity including the short-chain fatty acid butyrate, induce classical cell maturation effects on colon cancer cells in vitro, while overexpression of HDACs 1 and 2, inhibits intestinal cell differentiation. Consistent with these findings, we have now demonstrated that the class I HDAC, HDAC3, promotes cell proliferation and survival of colon cancer cells in vitro, and that it represses expression of p21, and the marker of colon cell differentiation, alkaline phosphatase. We have also demonstrated that HDAC3 expression is upregulated in human colon cancer and that it is maximally expressed in the proliferative compartment in normal mouse small intestine and colon, collectively implicating a role for this specific HDAC in maintaining intestinal cell proliferation and inhibition of cell maturation. Importantly, the expression pattern of HDAC3 parallels that of (B-catenin-TCF-MYC signaling, a major regulator of intestinal cell maturation, and the fundamental signaling pathway deregulated in colorectal tumorigenesis. Our primary hypothesis, therefore, is that (B-catenin-TCF-MYC signaling activates HDAC3 expression, which in turn, plays a role in maintaining cell proliferation and inhibiting differentiation of colonic and small intestinal epithelial cells. To directly test this, we will: 1. Determine whether HDAC3 expression is regulated by B-catenin-TCF-MYC signaling in intestinal cells. 2. Determine the effect of intestine-specific HDAC3 overexpression on cell maturation programs and tumor formation in vivo. We have generated a transgenic mouse (Villin-HDAC3- Tg), in order to overexpress HDAC3 in an intestinal-specific manner, and along the entire length of the crypt and crypt-villus axes. 3. Dissect the molecular mechanism by which HDAC3 mediates its phenotypic and transcriptional effects in colon cancer cells. Specifically, the role of the co-repressor proteins NCoR and SMRT and that of other class I and II HDACs in mediating the HDAC3 response will be addressed using an integrative gene expression profiling and ChIP on chip strategy. These studies are designed to provide insights into the role of HDAC3 in regulating intestinal cell maturation in vivo, and to define these effects in the context of existing paradigms of intestinal cell maturation and transformation. Additionally, given the current interest, and recently demonstrated efficacy of HDAC inhibitors in cancer treatment, these studies are designed to provide insights into the likelihood that this class of compounds will be efficacious in the treatment of colon cancer.

描述（由申请人提供）：转录辅阻遏物的组蛋白脱乙酰酶（HDAC）家族目前包含 18 个成员，正在成为结肠细胞成熟和转化的重要调节因子。例如，HDAC 活性抑制剂（包括短链脂肪酸丁酸酯）可在体外诱导结肠癌细胞的经典细胞成熟效应，而 HDAC 1 和 2 的过度表达会抑制肠细胞分化。与这些发现一致，我们现在已经证明，I 类 HDAC（HDAC3）可在体外促进结肠癌细胞的细胞增殖和存活，并抑制 p21 和结肠细胞分化标志物碱性磷酸酶的表达。我们还证明，HDAC3 表达在人类结肠癌中上调，并且在正常小鼠小肠和结肠的增殖区室中表达最大，共同暗示了这种特定 HDAC 在维持肠细胞增殖和抑制细胞成熟中的作用。重要的是，HDAC3 的表达模式与 (B-连环蛋白-TCF-MYC 信号传导，肠道细胞成熟的主要调节因子，以及结直肠肿瘤发生中失调的基本信号传导途径) 的表达模式相似。因此，我们的主要假设是 (B-连环蛋白-TCF-MYC 信号传导激活 HDAC3 表达，进而在维持细胞增殖和抑制结肠和小肠上皮细胞分化中发挥作用。为了直接测试这一点，我们将： 1. 确定是否。 HDAC3 表达受肠道细胞中的 B-catenin-TCF-MYC 信号传导调节。 2. 确定肠道特异性 HDAC3 过表达对体内细胞成熟程序和肿瘤形成的影响。），以便以肠道特异性方式过表达 HDAC3，并沿着隐窝和隐窝绒毛轴的整个长度。 3. 剖析 HDAC3 介导其作用的分子机制。结肠癌细胞的表型和转录效应。具体而言，将使用综合基因表达谱和 ChIP 芯片策略来解决共阻遏蛋白 NCoR 和 SMRT 以及其他 I 类和 II 类 HDAC 在介导 HDAC3 反应中的作用。这些研究旨在深入了解 HDAC3 在体内调节肠细胞成熟中的作用，并在现有的肠细胞成熟和转化范例的背景下定义这些作用。此外，考虑到目前人们对 HDAC 抑制剂在癌症治疗中的兴趣以及最近证明的功效，这些研究旨在深入了解此类化合物在结肠癌治疗中有效的可能性。