| Project/Area Number |
13670170
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Mie University |
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Principal Investigator |
WATANABE Masatoshi Mie University, Faculty of Medicine, Associate Prof., 医学部, 助教授 (90273383)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRAISHI Taizo Mie University, Faculty of Medicine, Prof., 医学部, 教授 (30162762)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | prostate cancer / epigenetics / nuclear receptor / methylation / acetylation |
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| Research Abstract |
Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. We have reported the importance of that epigenetic regulations including CpG methylation and histone acetylation in the regulation of the AR. In addition, these results suggested involvement of methylation in expression of nuclear receptors. The retinoic acid receptor (RAR) β gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Selective loss or down-regulation of RARβ mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RARβ2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RARβ2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2'-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RARβ2 in RARβ2-negative cells. These results suggest that the RARβ2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa. In addition, we found that methylation of the CD44 was related with prostate cancer progression. Our data shows that epigenetic mechanisms may be involved in expression of cancer-related genes.
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