Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours.
Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours.
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DOI：
10.1038/sj.bjc.6602422
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发表时间：
2005-03-28
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
缺氧是人类肿瘤发展和化疗耐药的关键因素。BNIP3是Bcl-2蛋白家族的促凋亡成员，参与缺氧诱导的细胞死亡。我们评估了BNIP3基因的表达和甲基化状态，以更好地了解其表达的表观遗传改变在造血肿瘤中的作用。在4个急性淋巴细胞白血病、1个多发性骨髓瘤和1个伯基特淋巴瘤细胞系中检测到bip3转录起始位点周围区域的甲基化，并且与该基因的沉默密切相关。用甲基转移酶抑制剂5-aza2 ' -脱氧胞苷（5-aza-dC）处理后，BNIP3的表达得以恢复，这证实了该基因因甲基化而被表观遗传失活。值得注意的是，使用5-aza2-dC重新表达BNIP3也恢复了缺氧介导的甲基化细胞系的细胞死亡。使用染色质免疫沉淀法评估的基因5 '区组蛋白H3的乙酰化与基因表达直接相关，与DNA甲基化呈负相关。在原发性肿瘤中，34例急性淋巴细胞白血病中有5例（15%）、35例急性骨髓性白血病中有6例（17%）和14例多发性骨髓瘤中有3例（21%）检测到BNIP3甲基化。这些结果表明，5 ' CpG岛的异常DNA甲基化和组蛋白去乙酰化在抑制造血肿瘤中BNIP3的表达中发挥了关键作用。
Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2′-deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5′ region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5′ CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.
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影响因子：
3.5
作者：
Baylin, SB;Esteller, M;Herman, JG
通讯作者：
Herman, JG
影响因子：
4.8
作者：
Kondo, Y;Issa, JPJ
通讯作者：
Issa, JPJ
影响因子：
14.9
作者：
Nguyen, CT;Gonzales, FA;Jones, PA
通讯作者：
Jones, PA
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1073/pnas.101617298
发表时间：
2001-04-24
影响因子：
11.1
作者：
Magdinier, F;Wolffe, AP
通讯作者：
Wolffe, AP