MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer
MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer
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DOI：
10.1002/ijc.22047
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发表时间：
2006-10-15
影响因子：
6.4
通讯作者：
Yonezawa, Suguru
中科院分区：
文献类型：
--
作者：
Yamada, Norishige;Hamada, Tomofumi;Yonezawa, Suguru
粘蛋白是高度糖化的蛋白质，在癌症发生中发挥重要作用。在胰腺肿瘤中，MUC2粘蛋白已被证明是一种肿瘤抑制因子，我们已报道MUC2是一个有利的预后因素。已知MUC2基因表达的调控是由DNA甲基化控制的，但组蛋白修饰对MUC2基因表达的作用尚不清楚。在此，我们首次报道了MUC2启动子区域的组蛋白H3修饰调节MUC2基因的表达。为了研究MUC2基因启动子区域的组蛋白修饰和DNA甲基化，我们用DNA甲基转移酶抑制剂5-氮杂胞苷(5-aza)、组蛋白去乙酰化酶抑制剂曲古菌素A(TSA)及其组合处理2株人胰腺癌细胞株PANC1(MUC2阴性)和BxPC3(MUC2阳性)。3种处理均可降低PANC1细胞的DNA甲基化水平，而组蛋白H3-K4/K9甲基化和H3-K9/K27乙酰化水平则与单独TSA和5-aza/TSA联合处理的BxPC3细胞相同。TSA和5-aza/TSA作用于PANC1细胞后，MUC2基因的表达水平明显升高，而5-aza单独作用仅有轻微的上调作用。我们的结果表明，5‘侧翼区的组蛋白H3修饰在MUC2基因的表达中起重要作用，可能影响DNA甲基化。了解这些密切相关的表观遗传学改变对于预测胰腺肿瘤患者的预后可能很重要。(C)2006年Wiley-Liss，Inc.
Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5' flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms. (c) 2006 Wiley-Liss, Inc.