| Budget Amount *help |
¥3,990,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications as well as DNA methylation However, the functional roles of the histone methyltransferases(HMT) in cancer remain unclear.
First, we examined histone modification changes and DNA methylation in hepatocellular carcinomas(HCC). Aberrant DNA methylation was frequently detected in all the HCC. Epigenetic states in HCC cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation and histone H3-lysine(K) 9 methylataon. However, silencing of the PGR and Erα genes was more closely related to H3-K27 methylation rather than DNA methylation Consistent with the alteration of histone status, higher expression of G9a and EZH2 was found in HCC than in non-cancerous liver tissues(P < 0.01) These data suggest that multiple epigenet
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ic silencing mechanisms are inappropriately active in HCC cells.
Next, We studied RNAi-based inhibition(knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the two HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. Karyotype analyses showed that this was due to an increased number of chromosomes in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in the G9a KD cells, while centrosomes were morphologically normal in control cells. These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers Less
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