| Budget Amount *help |
¥4,040,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥540,000)
Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Great effort has been directed towards understanding the mechanism of malignant transformation derived from genetic mutations. Nowadays, studies on epigenetic mutations in cancer are also required. In this project, we focused on epigenetics modulators (histone modification enzymes and histone variants), up-regulated during chemically induced hepatocarcinogenesis.
1. Effect of over expression of histone modification enzymes on the malignant transformation.
We identified histone modification enzymes, which induced during hepatocarcinogenesis by RT-PCR, DNA microarray, and Western blot analyses. One of them, histone acetyltransferase, regulated the transformation activity mediated by mutated ras oncogene. Histone deacetylase, one of other modulators, promoted anchorage independent growth in soft agarose.
2. Effect of over expression of histone modification enzymes on expression of the tumor marker gene.
Glutathione transferase placental form (GST-P) is specifically dramatically induced during
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hepatocarcinogenesis and recognized as a reliable tumor marker. Transcriptional factor Nrf2/MafK heterodimer is one of the most important positive regulators on GST-P expression during hepatocarcinogenesis. We revealed that one of histone acetyltransferase, which was over-expressed in nuclear extracts from livers including hyperplastic nodules, acted as a cofactor of Nrf2/MafK heterodimer and induced expression of GST-P.
3. Functional analysis of the histone variant in yeast.
We found that H2A.Z, one of histone variants, was induced during hepatocarcinogenesis. Tb gain insights of molecular function of H2A.Z, we generated a H2A.Z deletion strain in Saccharomyces cerevisiae. The H2A.Z deletion strain was sensitive to genotoxic reagents. Further, we observed the sensitivity to nickel compounds, which decrease acetylation levels of all four histones and increase ubiquitylation of H2A and H2B and dimethylation of H3 lysine 9, and revealed that the nickel toxicity appeared with the incorporation of H2AZ into chromatin mediated by the chromatin remodeling factor, but not acetylation of H2AZ. Less
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