Yamada Harumi, Takeshima Hideyuki, Fujiki Ryoji, Yamashita Satoshi, Sekine Shigeki, Ando Takayuki, Hattori Naoko, Okabe Atsushi, Yoshikawa Takaki, Obama Kazutaka, Katai Hitoshi, Kaneda Atsushi, Ushijima Toshikazu
Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104-0045, Tokyo, Japan; Department of Gastrointestinal Surgery, Faculty of Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-kawahara-cho, Sakyo-ku, 606-8507, Kyoto, Japan.
Division of Epigenomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104-0045, Tokyo, Japan.
Cancer Lett. 2022 Apr 28;532:215587. doi: 10.1016/j.canlet.2022.215587. Epub 2022 Feb 5.
The CpG island methylator phenotype (CIMP) is associated with prognosis and drug sensitivity in multiple cancer types. In gastric cancer, the CIMP is closely associated with Epstein-Barr virus (EBV) infection and AT-rich interactive domain 1A (ARID1A) mutations, a component of the SWI/SNF chromatin remodeling complex. However, the involvement of SWI/SNF defects in CIMP induction has been unclear. In this study, we demonstrate a causal role of ARID1A loss-of-function in CIMP induction. Mutations of SWI/SNF components, especially ARID1A, was associated with the CIMP, as well as EBV infection, in gastric cancers, and also in uterine endometrial and colorectal cancers, which are not affected by EBV infection. Genome-wide DNA methylation analysis showed that ARID1A knockout (KO) in cultured 293FT cells and gastric epithelial cells, GES1, induced aberrant DNA methylation of a substantial number of CpG sites. DNA methylation was induced at genomic regions with high levels of pre-existing histone H3 lysine 27 trimethylation (H3K27me3) and those with acquired H3K27me3 by ARID1A KO. These results showed that the ARID1A mutation induced aberrant DNA methylation, and this is likely to be one of the potential mechanisms of CIMP induction.
CpG岛甲基化表型（CIMP）与多种癌症类型的预后和药物敏感性相关。在胃癌中，CIMP与爱泼斯坦-巴尔病毒（EBV）感染以及富含AT的相互作用结构域1A（ARID1A）突变密切相关，ARID1A是SWI/SNF染色质重塑复合物的一个组成部分。然而，SWI/SNF缺陷在CIMP诱导中的作用尚不清楚。在本研究中，我们证明了ARID1A功能丧失在CIMP诱导中的因果作用。SWI/SNF组分的突变，尤其是ARID1A的突变，与胃癌以及子宫内膜癌和结直肠癌中的CIMP以及EBV感染相关，而子宫内膜癌和结直肠癌不受EBV感染影响。全基因组DNA甲基化分析表明，在培养的293FT细胞和胃上皮细胞GES1中敲除ARID1A（KO）会诱导大量CpG位点发生异常DNA甲基化。在预先存在高水平组蛋白H3赖氨酸27三甲基化（H3K27me3）的基因组区域以及通过敲除ARID1A获得H3K27me3的区域诱导了DNA甲基化。这些结果表明，ARID1A突变诱导了异常DNA甲基化，这可能是CIMP诱导的潜在机制之一。
