Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer.
Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer.
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DOI：
10.4161/cbt.8.1.7469
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发表时间：
2009-01
影响因子：
3.6
通讯作者：
Arnoletti JP
中科院分区：
文献类型：
--
作者：
Howard JH;Frolov A;Tzeng CW;Stewart A;Midzak A;Majmundar A;Godwin A;Heslin M;Bellacosa A;Arnoletti JP
MED 1是一种碱基切除修复酶，与错配修复蛋白MLH 1相互作用，通过结合甲基化DNA和修复自发脱氨事件来维持基因组完整性。MED 1突变与微卫星不稳定性和加速结直肠癌（CRC）肿瘤发生有关。我们认为，启动子甲基化可能是散发性CRC肿瘤发生过程中MED 1基因抑制的另一种表观遗传机制。在一组卵巢癌和结直肠癌细胞系中研究了MED 1启动子的甲基化状态。在亚硫酸氢盐处理后对MED 1启动子区域进行测序，序列分析鉴定了MED 1启动子内的CpG岛，其在MED 1表达低/降低的卵巢癌和结直肠癌细胞系中经常且优先甲基化（≥ 50%）。在体外逆转甲基化恢复MED 1表达。在结直肠癌患者中，当MED 1甲基化存在时，肿瘤和匹配的粘膜受到同等影响（平均甲基化频率为24%），甲基化与肿瘤分期之间没有相关性。无结直肠癌病史的患者甲基化频率显著降低（平均14%，p<0.05）。与对照组相比，在匹配的正常粘膜中观察到MED 1转录水平降低（中位数倍数差异8.0）。在粘膜和匹配的肿瘤之间观察到额外的表达降低（中值倍数降低4.4）。因此，MED 1启动子甲基化和基因沉默发生在散发性CRC患者中，代表CRC肿瘤发生的早期事件。在正常结肠粘膜中检测MED 1甲基化和基因抑制可能有助于在筛查过程中识别出患CRC风险较高的患者。
MED1 is a base excision repair enzyme that interacts with the mismatch repair protein MLH1 and maintains genomic integrity by binding methylated DNA and repairing spontaneous deamination events. MED1 mutations have been associated with microsatellite instability and accelerated colorectal cancer (CRC) tumorigenesis. We propose that promoter methylation may serve as an alternative epigenetic mechanism for MED1 gene suppression during sporadic CRC tumorigenesis. Methylation status of the MED1 promoter was investigated in a panel of ovarian and colorectal cancer cell lines. The MED1 promoter region was sequenced following bisulfite treatment and sequence analysis identified a CpG island within the MED1 promoter which is frequently and preferentially methylated (≥ 50%) in ovarian and colorectal cancer cell lines with low/reduced MED1 expression. In vitro reversal of methylation restored MED1 expression. In colorectal cancer patients, when MED1 methylation was present, both tumor and matched mucosa were affected equally (mean frequency of methylation 24%) and there was no correlation between methylation and tumor stage. Patients without history of CRC showed significantly lower frequency of methylation (mean 14%, p<0.05). Decreased MED1 transcript levels were observed in matched normal mucosa when compared to controls (median fold difference 8.0). Additional decreased expression was seen between mucosa and matched tumor (median fold decrease 4.4). Thus, MED1 promoter methylation and gene silencing occur in sporadic CRC patients and represent an early event in CRC tumorigenesis. Detection of MED1 methylation and gene suppression in normal colon mucosa may contribute to identifying patients at higher risk of developing CRC during screening procedures.
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DOI：
10.1073/pnas.2334585100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Cortellino, S;Turner, D;Bellacosa, A
通讯作者：
Bellacosa, A
影响因子：
30.8
作者：
Cameron, EE;Bachman, KE;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
8
作者：
Sansom, OJ;Bishop, SM;Clarke, AR
通讯作者：
Clarke, AR
影响因子：
11.5
作者：
Makarla, PB;Saboorian, MH;Schorge, JO
通讯作者：
Schorge, JO
影响因子：
3.6
作者：
Mukherjee, Shibani;Frolova, Natalya;Frost, Andra R.
通讯作者：
Frost, Andra R.