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GASC1通过NOTCH1启动子去甲基化促进食管鳞状细胞癌的干性。

GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation.

作者信息

Jia Ruinuo, Yang Li, Yuan Xiang, Kong Jinyu, Liu Yiwen, Yin Weijiao, Gao Shegan, Zhang Yi

机构信息

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

出版信息

J Oncol. 2019 Mar 26;2019:1621054. doi: 10.1155/2019/1621054. eCollection 2019.

DOI:10.1155/2019/1621054
PMID:31031809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6457298/
Abstract

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 and . 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.

摘要

食管鳞状细胞癌（ESCC）的发病率在中国最高。癌症干细胞在肿瘤进展中起关键作用。鳞状细胞癌中扩增的基因1（GASC1）对于维持胚胎干细胞的自我更新和分化潜能至关重要。本研究旨在揭示GASC1对ESCC干性的影响及机制。通过体内和体外实验评估了GASC1在ESCC中的生物学功能。进行染色质免疫沉淀（ChIP）实验以确定GASC1在NOTCH1表观遗传调控中的分子机制。我们发现，GASC1在低分化ESCC细胞和组织中的表达增加。GASC1水平高的ESCC患者生存率显著更差。纯化的醛脱氢酶（ALDH）阳性ESCC细胞中GASC1的表达明显高于ALDH阴性细胞。GASC1阻断后，ESCC的干性显著降低。此外，GASC1的阻断通过增加NOTCH1启动子H3K9me2和H3K9me3来降低NOTCH1的表达。而且，转染NOTCH1过表达慢病毒载体后，GASC1阻断后受损的干性可以得到逆转。GASC1通过NOTCH1启动子去甲基化促进ESCC细胞的干性。因此，GASC1/NOTCH1信号通路可能是治疗ESCC患者的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/f1a8ca1825d3/JO2019-1621054.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e6f37da5895d/JO2019-1621054.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/80158584aaab/JO2019-1621054.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e1398d472be8/JO2019-1621054.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/256dd12d2b0b/JO2019-1621054.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/1ceabfde3f94/JO2019-1621054.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e99f72c5a88b/JO2019-1621054.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/f1a8ca1825d3/JO2019-1621054.007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e6f37da5895d/JO2019-1621054.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/80158584aaab/JO2019-1621054.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e1398d472be8/JO2019-1621054.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/256dd12d2b0b/JO2019-1621054.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/1ceabfde3f94/JO2019-1621054.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/e99f72c5a88b/JO2019-1621054.006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/155d/6457298/f1a8ca1825d3/JO2019-1621054.007.jpg

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