Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer.
Epigenetic repression of DNA mismatch repair by inflammation and hypoxia in inflammatory bowel disease-associated colorectal cancer.
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DOI：
10.1158/0008-5472.can-09-1285
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Lipkin SM
中科院分区：
文献类型：
--
作者：
Edwards RA;Witherspoon M;Wang K;Afrasiabi K;Pham T;Birnbaumer L;Lipkin SM
散发性人类错配修复缺陷型结直肠癌(MMR缺陷型结直肠癌)占∼的12.5%。MMR缺陷型大肠癌的典型特征是右侧定位、多灶性、粘液组织学和淋巴细胞浸润。然而，生殖系MMR缺陷小鼠模型中的肿瘤缺乏这些组织病理学特征。缺乏异三聚体G蛋白α亚单位GIα2的小鼠会患上慢性结肠炎和多灶性右侧癌症，表现为粘液组织病理学，类似于人类MMR缺陷型结直肠癌。年轻的GIMMS2-/-结肠上皮有正常的α表达，但在炎症后选择性地丢失MLH1PMS2的表达。GIα2-/-癌症具有微卫星不稳定性。MLH1在表观遗传学上是沉默的，不是由于启动子的超甲基化，而是由于组蛋白乙酰化的减少。慢性炎症的GIα2-/-结肠粘膜含有片状低氧，低氧标志物DEC-1和BNIP3的隐窝表达增加。染色质免疫沉淀发现，在缺氧的YAMC细胞和结肠炎GIα2/-隐窝中，转录抑制因子DEC-1与近端MLH1启动子的结合增加。用组蛋白脱乙酰酶抑制剂异羟肟酸(SAHA)治疗GIMLH2-/-小鼠可显著降低结肠炎的活性，并挽救隐窝上皮细胞中α的表达，这与乙酰H3水平升高和MLH1近端启动子结合减少有关，与HDAC依赖的机制一致。这些数据将慢性缺氧性炎症、表观遗传学MMR蛋白下调、MMR-CRC的发展联系在一起，是第一个体细胞获得性MMR缺陷CRC的小鼠模型。
Sporadic human mismatch repair-deficient colorectal cancers (MMR-deficient CRC) account for ∼12.5% of all cases of colorectal cancer. MMR-deficient CRCs are classically characterized by right sided location, multifocality, mucinous histology and lymphocytic infiltration. However, tumors in germline MMR deficient mouse models lack these histopathologic features. Mice lacking the heterotrimeric G-protein alpha subunit Giα2 develop chronic colitis and multifocal, right sided cancers with mucinous histopathology, similar to human MMR-deficient CRC. Young Giα2-/- colonic epithelium has normal MMR expression but selectively loses MLH1 and consequently PMS2 expression following inflammation. Giα2-/- cancers have microsatellite instability. MLH1 is epigenetically silenced, not by promoter hypermethylation, but by decreased histone acetylation. Chronically inflamed Giα2-/- colonic mucosa contains patchy hypoxia, with increased crypt expression of the hypoxia markers DEC-1 and BNIP3. Chromatin immunoprecipitation identified increased binding of the transcriptional repressor DEC-1 to the proximal MLH1 promoter in hypoxic YAMC cells and colitic Giα2-/- crypts. Treating Giα2-/- mice with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) significantly decreased colitis activity, and rescued MLH1 expression in crypt epithelial cells that was associated with increased acetyl H3 levels and decreased DEC-1 binding at the proximal Mlh1 promoter, consistent with an HDAC-dependent mechanism. These data link chronic hypoxic inflammation, epigenetic MMR protein downregulation, the development of MMR-CRC, and is the first mouse model of somatically acquired MMR-deficient CRC.