A Transcriptional Regulatory Role of the THAP11-HCF-1 Complex in Colon Cancer Cell Function
A Transcriptional Regulatory Role of the THAP11-HCF-1 Complex in Colon Cancer Cell Function
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DOI：
10.1128/mcb.06033-11
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发表时间：
2012-05-01
影响因子：
5.3
通讯作者：
Chakravarti, Debabrata
中科院分区：
文献类型：
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作者：
Parker, J. Brandon;Palchaudhuri, Santanu;Chakravarti, Debabrata
最近发现的死亡相关蛋白（THAP）结构域是一个非典型的锌指基序，具有序列特异性的DNA结合活性。新兴的数据表明，THAP蛋白可能在染色质依赖的过程中发挥作用，包括转录调控，但大多数THAP蛋白在正常和异常的细胞过程中的作用仍然在很大程度上未知。在这项工作中，我们确定THAP 11作为一个转录调节差异表达在人类结肠癌。人结肠癌的免疫组织化学分析显示，原发肿瘤和转移瘤中THAP 11表达增加。SW 620结肠癌细胞中THAP 11的敲低导致细胞增殖显著降低，并且这些细胞中的基因表达谱鉴定了由80个差异表达基因组成的新基因集，其中70%被THAP 11敲低去抑制。发现THAP 11与转录辅助调节因子HCF-1（宿主细胞因子1）物理相关，并将HCF-1募集到靶向启动子。重要的是，THAP 11介导的基因调控及其染色质缔合需要HCF-1，而HCF-1在这些基因上的募集需要THAP 11。总的来说，这些数据提供了人类结肠癌细胞中THAP 11依赖性基因表达的第一个表征，并表明THAP 11-HCF-1复合物可能是人类结肠癌中重要的转录和细胞生长调节因子。
The recently identified Thanatos-associated protein (THAP) domain is an atypical zinc finger motif with sequence-specific DNA-binding activity. Emerging data suggest that THAP proteins may function in chromatin-dependent processes, including transcriptional regulation, but the roles of most THAP proteins in normal and aberrant cellular processes remain largely unknown. In this work, we identify THAP11 as a transcriptional regulator differentially expressed in human colon cancer. Immunohistochemical analysis of human colon cancers revealed increased THAP11 expression in both primary tumors and metastases. Knockdown of THAP11 in SW620 colon cancer cells resulted in a significant decrease in cell proliferation, and profiling of gene expression in these cells identified a novel gene set composed of 80 differentially expressed genes, 70% of which were derepressed by THAP11 knockdown. THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters. Importantly, THAP11-mediated gene regulation and its chromatin association require HCF-1, while HCF-1 recruitment at these genes requires THAP11. Collectively, these data provide the first characterization of THAP11-dependent gene expression in human colon cancer cells and suggest that the THAP11-HCF-1 complex may be an important transcriptional and cell growth regulator in human colon cancer.