Epigenetic silencing of BTB and CNC homology 2 and concerted promoter CpG methylation in gastric cancer
Epigenetic silencing of BTB and CNC homology 2 and concerted promoter CpG methylation in gastric cancer
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DOI：
10.1016/j.canlet.2014.05.009
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发表时间：
2014-09-01
期刊：
影响因子：
9.7
通讯作者：
Kim, Yong Sung
中科院分区：
文献类型：
--
作者：
Haam, Keeok;Kim, Hee-Jin;Kim, Yong Sung
BTB和CnC同源基因2(BACH2)是一种淋巴特异性转录因子，在B细胞发育中具有重要作用。编码BACH2的单个基因座内的遗传多态与各种自身免疫性疾病和过敏有关。在这项研究中，限制性里程碑式的基因组扫描显示，在胃癌细胞系和原发胃肿瘤中，覆盖BACH2启动子的CpG岛上的NotI位点发生了甲基化。BACH2启动子甲基化水平在52%(43/83)的原发胃肿瘤中升高，且BACH2高甲基化与基因表达降低显著相关。用5-氮杂-2‘-脱氧胞苷和/或曲古菌素治疗。在BACH2沉默的胃癌细胞系中恢复BACH2的表达，并使用短发夹状RNA(即RNA干扰)敲除BACH2(即RNA干扰)可促进胃癌细胞的增殖。临床病理资料显示肠型胃癌(27/44，61%)较弥漫型胃癌(13/50，26%)表达降低(P<；0.001)。此外，在一组给定的胃肿瘤中，BACH2启动子甲基化与先前识别的靶点，如LRRC3B、LIMS2、PRKD1和POPDC3的甲基化平行。我们认为许多启动子的协同甲基化在促进胃肿瘤的形成中起作用，甲基化的启动子位点可能是治疗的靶点，例如最近引入的表观遗传编辑技术。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription factor with a prominent role in B-cell development. Genetic polymorphisms within a single locus encoding BACH2 are associated with various autoimmune diseases and allergies. In this study, restriction landmark genomic scanning revealed methylation at a NotI site in a CpG island covering the BACH2 promoter in gastric cancer cell lines and primary gastric tumors. Increased methylation of the BACH2 promoter was observed in 52% (43/83) of primary gastric tumors, and BACH2 hypermethylation was significantly associated with decreased gene expression. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin. A restored BACH2 expression in BACH2-silenced gastric cancer cell lines, and knockdown of BACH2 using short hairpin RNA (i.e. RNA interference) increased cell proliferation in gastric cancer cells. Clinicopathologic data showed that decreased BACH2 expression occurred significantly more frequently in intestinal-type (27/44, 61%) compared with diffuse-type (13/50, 26%) gastric cancers (P < 0.001). Furthermore, BACH2 promoter methylation paralleled that of previously identified targets, such as LRRC3B, LIMS2, PRKD1 and POPDC3, in a given set of gastric tumors. We propose that concerted methylation in many promoters plays a role in accelerating gastric tumor formation and that methylated promoter loci may be targets for therapeutic treatment, such as the recently introduced technique of epigenetic editing. (C) 2014 Elsevier Ireland Ltd. All rights reserved.