DACT2 Epigenetic Stimulator Exerts Dual Efficacy for Colorectal Cancer Prevention and Treatment
DACT2 Epigenetic Stimulator Exerts Dual Efficacy for Colorectal Cancer Prevention and Treatment
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DACT2表观遗传刺激器发挥结直肠癌预防和治疗的双重功效
DOI：
10.1016/j.phrs.2017.11.032
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发表时间：
2018-03-01
影响因子：
9.3
通讯作者：
Liu, Zhongqiu
中科院分区：
文献类型：
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作者：
Lu, Linlin;Wang, Ying;Liu, Zhongqiu
DACT2 是多种肿瘤中的抑癌基因，经常通过高甲基化而下调。我们发现 DACT2 基因表达在我们的临床结直肠癌 (CRC) 组织中显着沉默 (P = 0.002，n = 8)，TCGA 数据显示 DACT2 高甲基化与 CRC 不良预后相关 (P = 0.0129，HR = 0.2153，n = 248)。因此，通过筛选 12 种营养化合物，我们的目的是找到一种有效的 DACT2 表观遗传刺激剂，以确定 DACT2 表观遗传恢复是否可以逆转 CRC 肿瘤发生。我们发现山奈酚在三种 CRC 细胞（HCT116、HT29 和 YB5）中显着增加 DACT2 表达高达 3.47 倍。此外，山奈酚显着降低了 DACT2 甲基化（范围：19.58%-67.00%，P < 0.01），同时通过直接与 DNA 甲基转移酶 DNMT1 结合，使未甲基化的 DACT2 增加了 13.72 倍（P < 0.01）。通过表观遗传重新激活 DACT2 转录，山奈酚显着抑制核 β-catenin 表达，从而失活 Wnt/β-catenin 通路，从而限制 CRC 细胞的增殖和迁移。此外，在AOM/DSS诱导的CRC肿瘤发生中，山奈酚去甲基化的DACT2有效降低肿瘤负荷（范围：50.00%-73.52%，P < 0.05）。通过确定新型 DACT2 去甲基化刺激剂的化学预防和化疗功效，我们证明 DACT2 表观遗传恢复可以成功减缓和逆转 CRC 肿瘤发生。 (C) 2017 年作者。由爱思唯尔有限公司出版
DACT2, a tumor suppressor gene in various tumors, is frequently down-regulated via hypermethylation. We found DACT2 gene expressions were dramatically silenced (P = 0.002, n = 8) in our clinical colorectal cancer (CRC) tissues, and TCGA data revealed DACT2 hypermethylation correlated to CRC poor prognosis (P = 0.0129, HR = 0.2153, n = 248). Thus, by screening twelve nutritional compounds, we aimed to find out an effective DACT2 epigenetic stimulator to determine whether DACT2 epigenetic restoration could reverse CRC tumorigenesis. We found that kaempferol significantly increased DACT2 expressions up to 3.47-fold in three CRC cells (HCT116, HT29, and YB5). Furthermore, kaempferol remarkably decreased DACT2 methylation (range: 19.58%-67.00%, P < 0.01), while increased unmethylated DACT2 by 13.72-fold (P < 0.01) via directly binding to DNA methyltransferases DNMT1. By epigenetic reactivating DACT2 transcription, kaempferol notably inhibited nuclear beta-catenin expression to inactivate Wnt/beta-catenin pathway, which consequently restricted CRC cells proliferation and migration. Moreover, in AOM/DSS-induced CRC tumorigenesis, kaempferol-demethylated DACT2 effectively decreased tumor load (range: 50.00%-73.52%, P < 0.05). By determining the chemopreventive and chemotherapeutic efficacy of a novel DACT2 demethylating stimulator, we demonstrated that DACT2 epigenetic restoration could successfully slow down and reverse CRC tumorigenesis. (C) 2017 The Authors. Published by Elsevier Ltd.