GLI1 Interferes with the DNA Mismatch Repair System in Pancreatic Cancer through BHLHE41-Mediated Suppression of MLH1
GLI1 Interferes with the DNA Mismatch Repair System in Pancreatic Cancer through BHLHE41-Mediated Suppression of MLH1
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DOI：
10.1158/0008-5472.can-13-2008
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发表时间：
2013-12-15
期刊：
影响因子：
11.2
通讯作者：
Kasai, Kenji
中科院分区：
文献类型：
--
作者：
Inaguma, Shingo;Riku, Miho;Kasai, Kenji
错配修复（MMR）系统对于DNA复制的保真度是不可或缺的，DNA复制的保真度的受损倾向于许多类型的癌症的发展和进展。迄今为止，已证明Hedgehog信号通路的关键分子GLI 1转录因子可调节多种癌症（包括胰腺导管腺癌（PDAC））中对多种癌细胞特性至关重要的几种基因的表达，但GLI 1是否可以控制MMR系统尚不清楚。在这里，我们发现GLI 1和GLI 2间接抑制PDAC细胞中MLH 1的表达。通过对GLI 1靶基因的筛选，我们发现GLI 1和GLI 2通过启动子中的GLI-binding位点激活碱性螺旋-环-螺旋型抑制基因BHLHE 41/DEC 2/SHARP 1的表达。与先前报道的BHLHE 41抑制MLH 1启动子活性一致，我们发现GLI 1的激活导致MLH 1的BHLHE 41依赖性抑制，并且GLI 1和GLI 2的双敲低相反地增加PDAC细胞中的MLH 1蛋白。使用基于TALEN的MLH 1基因修饰，我们进一步表明GLI 1表达确实与对甲基化剂甲基亚硝基脲的耐受性增加以及MLH 1的较低拷贝数状态相关。最后，在PDAC细胞和胰腺癌前病变中，GLI 1表达与BHLHE 41呈正相关，与MLH 1呈负相关。基于这些结果，我们提出GLI 1抑制MMR活性，并可能有助于PDAC的发生和进展。(C)2013年AACR。
The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/ SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. (C) 2013 AACR.