GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation
GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation
复制标题
GASC1通过NOTCH1启动子去甲基化促进食管鳞状细胞癌的干细胞性
DOI：
10.1155/2019/1621054
复制
发表时间：
2019-01-01
影响因子：
--
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Jia, Ruinuo;Yang, Li;Zhang, Yi
食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）是我国发病率最高的肿瘤。癌症干细胞在肿瘤进展中起关键作用。鳞状细胞癌基因扩增产物1（GASC 1）是维持胚胎干细胞自我更新和分化潜能的关键基因。本研究旨在揭示GASC 1基因对ESCC干性的影响及其机制。在体外和体内研究GASC 1在食管鳞癌中的生物学功能。通过ChIP分析来确定GASC 1在NOTCH 1的表观遗传调控中的分子机制。我们发现GASC 1在低分化食管鳞癌细胞和组织中表达增加。GASC 1水平高的ESCC患者的生存率明显较差。纯化的ALDH+ ESCC细胞中的GASC 1表达显著高于ALDH−细胞。GASC 1阻断后ESCC的干性显着降低。此外，GASC 1的阻断通过增加NOTCH 1启动子H3 K9 me 2和H3 K9 me 3来降低NOTCH 1表达。此外，在转染NOTCH 1过表达慢病毒载体后，GASC 1阻断后受损的干性可以逆转。GASC 1通过NOTCH 1启动子去甲基化促进ESCC细胞的干性。因此，GASC 1/NOTCH 1信号通路可能是治疗ESCC患者的潜在治疗靶点。
The highest incidence of esophageal squamous cell carcinoma (ESCC) occurs in China. Cancer stem cells play key roles for tumor progression. Gene amplified in squamous cell carcinoma 1 (GASC1) is essential to maintain self-renewal and differentiation potential of embryonic stem cells. This study aimed to reveal the effect and mechanism of GASC1 on ESCC stemness. The biological function of GASC1 in ESCC was evaluated both in vitro and in vivo. ChIP assay was performed to determine the molecular mechanism of GASC1 in epigenetic regulation of NOTCH1. We found that GASC1 expression was increased in poor differentiated ESCC cells and tissues. ESCC patients with a high level of GASC1 presented a significantly worse survival rate. GASC1 expression in purified ALDH+ ESCC cells was significantly higher than that in ALDH− cells. The stemness of ESCC was dramatically decreased after GASC1 blockade. Furthermore, blockade of GASC1 decreased NOTCH1 expression via increase of NOTCH1 promoter H3K9me2 and H3K9me3. Moreover, the impaired stemness after blockade of GASC1 could be reversed after transfection of NOTCH1 overexpression lentiviral vector. GASC1 promoted stemness in ESCC cells via NOTCH1 promoter demethylation. Therefore, GASC1/NOTCH1 signaling might be a potential therapeutic target for the treatment of ESCC patients.