CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers
CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers
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DOI：
10.3892/ijo_00000235
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发表时间：
2009-04-01
影响因子：
5.2
通讯作者：
Ozawa, Shogo
中科院分区：
文献类型：
--
作者：
Habano, Wataru;Gamo, Toshie;Ozawa, Shogo
细胞色素 P450 (CYP) 1A1 (CYP1A1) 和 CYP1B1（二恶英诱导型 CYP1）与肝外组织的癌变相关。 CYP1B1 在激素反应性组织的癌变中起重要作用，其中 CYP1B1 水平相当高。尽管在与激素反应无关的癌症中也观察到这些酶的异常表达，但它们在致癌过程中的作用尚未完全了解。我们检查了 7 个结直肠癌细胞系和 40 个原发性结直肠癌中 CYP1B1 和 CYP1A1 基因 5' 侧翼区域内 CpG 岛的 DNA 甲基化状态。通过亚硫酸氢盐修饰的直接测序，在 2 个细胞系（SW48 和 Caco-2）和 2 个（5%）癌症中检测到 CYP1B1 基因甲基化，但在相应的正常组织中未检测到。用 5-aza-2'-deoxycytidine 处理细胞后发现，SW48 和 Caco-2 细胞中 CYP1B1 mRNA 水平明显增加，而甲基化等位基因的数量减少。只有 HT29 细胞显示 CYP1A1 mRNA 明显增加，尽管这些细胞系之间的甲基化状态没有明显差异。这些细胞系的芳基碳氢化合物受体 (AhR) 和 AhR 核易位蛋白 (ARNT) 的 mRNA 水平均未显示显着变化，而已知这两种受体可直接激活 CYP1 转录。这一观察结果表明，CYP1B1 的表达而非 CYP1A1 的表达因启动子甲基化而下调，而不是 AhR/ARNT 表达的降低。总之，CYP1B1 启动子区域的 CpG 甲基化在某些结直肠癌的发生过程中通过表观遗传调节 CYP1B1 的表达。此外，具有异常 CYP1B1 表达的癌症可能表现出对原致癌物代谢和化疗的反应改变。
Cytochrome P450 (CYP) 1A1 (CYP1A1) and CYP1B1, dioxin-inducible CYP1s, are associated with carcinogenesis in extrahepatic tissues. CYP1B1 is featured in carcinogenesis of hormone-responsive tissues, where the CYP1B1 level is considerably high. Although aberrant expression of these enzymes is also observed in cancers that are not related to hormone response, their roles in carcinogenesis are not yet fully understood. We examined DNA methylation status of the CpG islands within the 5'-flanking region of the CYP1B1 and CYP1A1 genes in 7 colorectal cancer cell lines and 40 primary colorectal cancers. By bisulfite-modified direct sequencing, CYP1B1 gene methylation was detected in 2 cell lines (SW48 and Caco-2) and 2 (5%) cancers, but not in corresponding normal tissues. Treatment of the cells with 5-aza-2'-deoxycytidine revealed a clear increase in the CYP1B1 mRNA levels in SW48 and Caco-2 cells, while the amount of methylated alleles decreased. Only HT29 cells showed a clear increase in CYP1A1 mRNA, although there were no apparent differences in methylation status among these cell lines. None of these cell lines showed significant change in mRNA levels of aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT), which are known to directly activate CYP1 transcription. This observation suggested that expression of CYP1B1, but not CYP1A1, was downregulated by promoter methylation rather than decreased expression of AhR/ARNT. In conclusion, CpG methylation of the CYP1B1 promoter region epigenetically regulates CYP1B1 expression during development of some colorectal cancers. Moreover, cancers with aberrant CYP1B1 expression might show altered response to procarcinogen metabolism and chemotherapy.