Abnormal methylation of histone deacetylase genes: implications on etiology and epigenetic therapy of astrocytomas.
Abnormal methylation of histone deacetylase genes: implications on etiology and epigenetic therapy of astrocytomas.
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发表时间：
2011-04
影响因子：
2
通讯作者：
M. Gomes;K. Borges;D. Moreno;Rosane Gomes Queiroz;H. Machado;C. Carlotti;C. Scrideli;L. Tone
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作者：
M. Gomes;K. Borges;D. Moreno;Rosane Gomes Queiroz;H. Machado;C. Carlotti;C. Scrideli;L. Tone
越来越多的证据表明表观遗传学改变参与了星形细胞瘤的病因学。在本研究中，我们的目的是评估组蛋白去乙酰化酶基因（HDAC）的DNA甲基化与星形细胞瘤病因的关系，以及表观遗传学治疗的意义。材料和方法通过甲基化特异性定量PCR（MSED-qPCR）评估29个肿瘤样本（星形细胞瘤I级、III级和IV级）和胶质母细胞瘤细胞系U87、U251、U343、SF 188和T98 G中HDAC 4、HDAC 5和HDAC 6基因的甲基化。结果：与非肿瘤性脑样本（p=0.0007）和胶质母细胞瘤细胞系（p=0.001）相比，在星形细胞瘤中观察到HDAC 5基因甲基化显著增加。与胶质母细胞瘤细胞系相比，证明了异基因甲基化模式。在体外用地西他滨处理不同的细胞系后，观察到对甲基化和基因表达的不同影响。结论HDAC基因异常甲基化与星形细胞瘤的发病有关，并提示基因座特异性表观遗传个体间性可能与地西他滨治疗反应的差异有关。
BACKGROUND A growing body of evidence has revealed the involvement of epigenetic alterations in the etiology of astrocytomas. In the present study, we aimed to evaluate the association of DNA methylation of histone deacetylase genes (HDAC) with the etiology of astrocytoma, and the implications for epigenetic therapy. MATERIALS AND METHODS Methylation of the HDAC4, HDAC5 and HDAC6 genes was assessed in 29 tumor samples (astrocytomas grades I, III, and IV) and in the glioblastoma cell lines U87, U251, U343, SF188, and T98G by methylation-specific quantitative PCR (MSED-qPCR). RESULTS Significantly increased methylation of the HDAC5 gene was observed in astrocytomas when compared to non-neoplastic brain samples (p=0.0007) and to glioblastomas cell lines (p=0.001). A heterogenic methylation pattern was evidenced when compared to the glioblastoma cell lines. Distinct effects on methylation and gene expression were observed after in vitro treatment of the different cell lines with decitabine. CONCLUSION Our results suggest that abnormal methylation of HDAC genes is involved in the etiology of astrocytomas and indicate that loci-specific epigenetic interindividualities might be associated to the differential responses to treatment with decitabine.