文章基本信息

标题：Histone Methyltransferase PR-Set7 and Histone Variant H2A.Z, Induced during Hepatocarcinogenesis, Repress the Promoter Activity of the Tumor Marker Gene and the Ras-Induced Colony Formation Activity
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作者：Hiroshi Hashizume ; Urara Gomita ; Masayoshi Imagawa 等
期刊名称：Journal of Health Science
印刷版ISSN：1344-9702
电子版ISSN：1347-5207
出版年度：2011
卷号：57
期号：3
页码：264-273
DOI：10.1248/jhs.57.264
出版社：The Pharmaceutical Society of Japan
摘要：Genetic and epigenetic studies are required to understand molecular mechanisms of carcinogenesis and tumorigenesis. Although alterations of DNA methylation and histone modification profiles are observed in cancer cells, the knowledge of the epigenetic regulatory factors involved in carcinogenesis is insufficient. In this study, we showed that the histone variant, H2a.z , and the histone methyltransferase, Pr-set7/Set8/KMT5a , were up-regulated during chemically induced hepatocarcinogenesis. During this process, the glutathione S -transferase placental form (GST-P), which is completely repressed in normal liver, is strongly induced and is therefore an excellent tumor marker. Reporter analysis performed using the regulatory region of the Gst-p gene revealed that H2A.Z and PR-SET7 repressed Gst-p promoter activity. The enhancer element responsible for hepatocarcinogenic-specific gene expression was required for repression by H2A.Z, and the negative regulation by PR-SET7 mediated the regulatory element but not the enhancer. Furthermore, we examined the effects of overexpression of H2A.Z and PR-SET7 on the colony formation activity of mouse NIH-3T3 cells grown on a soft agarose medium. Colony formation based on anchoring independent cell growth is a feature of malignant transformed cells. These factors did not exhibit colony formation activity but repression of the ras oncogene induced this activity. PR-SET7 suppressed RAS^val12-mediated colony formation through methyltransferase activity. These results suggest that H2a.z and Pr-set7 that are induced during hepatocarcinogenesis may function as carcinogenesis suppressors.
关键词：histone variant;histone methyltransferase;epigenetics;anchorage-independent growth;tumor marker gene;hepatocarcinogenesis