Carcinogenesis, 2013, 34(8):1756-63.

DNA methylation and histone modifications of Wnt genes by genistein during colon cancer development

Yukun Zhang, Qian Li, Hong Chen

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

This study aims to elucidate the epigenetic mechanisms by which genistein (GEN) maintains a normal level of WNT genes during colon cancer development. We have reported that soy protein isolate (SPI) and GEN repressed WNT signaling, correlating with the reduction of pre-neoplastic lesions in rat colon. We hypothesized that SPI and GEN induced epigenetic modifications on Sfrp2, Sfrp5 and Wnt5a genes, suppressing their gene expression induced by azoxymethane (AOM), a chemical carcinogen, to the similar level as that of pre-AOM period. We identified that in the post-AOM period, histone H3 acetylation (H3Ac) was downregulated by SPI and GEN at the promoter region of Sfrp2, Sfrp5 and Wnt5a, which paralleled with the reduced binding of RNA polymerase II. Nuclear level of histone deacetylase 3 was enhanced by SPI and GEN. The diets suppressed the trimethylation of histone H3 Lysine 9 (H3K9Me3) and the phosphorylation of histone H3 Serine 10 (H3S10P). Methylation of the specific region of Sfrp2, Sfrp5 and Wnt5a genes was increased by SPI and GEN, which was inversely correlated with the reduction of gene expression. Bisulfite sequencing further confirmed that dietary GEN induced DNA methylation at CpG island of the promoter region of Sfrp5. Importantly, this region includes a fragment that had decreased H3Ac. Here, we present a potential epigenetic mechanism by which dietary GEN controls the responses of WNT genes during carcinogen induction, which involves DNA methylation, histone modifications and their interactions at the regulatory region of gene.

英国《癌变》，2013年4月

在结肠癌发展期间由金雀异黄素对 Wnt 基因进行 DNA 甲基化和组蛋白改性

张玉坤，李倩，陈宏

美国伊利诺伊大学厄巴纳-尚佩恩分校食品科学和人类营养学院

本研究旨在阐明在结肠肿瘤发展过程中金雀异黄素 （GEN）使WNT 基因保持正常水平的表观遗传机制。我们报道了大豆蛋白分离物(SPI) 和GEN抑制了 WNT 信号，与减少大鼠结肠癌前期肿瘤性病变相关。我们假设 SPI 和GEN诱导 Sfrp2、 Sfrp5 和 Wnt5a 基因的表观遗传改性，抑制由氧化偶氮甲烷 (AOM，一种化学致癌物质) 诱导的基因表达，直到与AOM之前相近的水平。我们发现，在AOM 之后，组蛋白 H3 乙酰化 (H3Ac) 被Sfrp2、 Sfrp5 和 Wnt5a启动子区域的SPI 和GEN下调，与绑定RNA 聚合酶 II的减弱同时发生。组蛋白去乙酰化酶 3 的细胞核水平由SPI 和GEN提高。饮食抑制了组蛋白 H3 赖氨酸 9 (H3K9Me3) 的 三甲基化和组蛋白 H3 丝氨酸 10 (H3S10P)的磷酸化。Sfrp2、 Sfrp5 和 Wnt5a 基因特定区域的甲基化由 SPI 和GEN增加，与基因表达的减少呈负相关。亚硫酸氢盐测序进一步证实饮食GEN在Sfrp5启动子区域的CpG 岛上诱导 DNA 甲基化。重要的是，这一区域包括了减少了的H3Ac 的片段。在这里，我们提出在致癌物诱导，涉及 DNA 甲基化、 组蛋白修饰和基因控制区域的相互作用期间，膳食GEN控制 WNT 基因响应的一种潜在表观遗传机制。