TY - JOUR
T1 - Demethylation of the RB1 promoter concomitant with reactivation of TET2 and TET3 impairs gastric carcinogenesis in K19-Wnt1/C2mE transgenic mice
AU - Cao, Donghui
AU - Jia, Zhifang
AU - Wu, Yanhua
AU - Su, Tongrong
AU - Zhao, Dan
AU - Wu, Menghui
AU - Tsukamoto, Tetsuya
AU - Oshima, Masanobu
AU - Jiang, Jing
AU - Cao, Xueyuan
N1 - Funding Information:
This research was funded by National Natural Science Foundation of China (No. 81673145 ), the Scientific and Technological Development Program of Jilin Province (No. 20200201326JC ), the National Key Research and Development Program of China (No. 2018YFC1312100 ) and the Continuing Foundation for NSFC from the First Hospital of Jilin University (No. 2020-CXM-07 ).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - Aberrant methylation of promoter CpG islands (CGIs) can inactivate the expression of many tumor suppressor genes and play an important role in the carcinogenesis of gastric cancer. The tumor suppressor gene RB1, which encodes a cell cycle regulator, is hypermethylated and downregulated in multiple kinds of cancer. Activation of RB1 expression through DNA demethylation is a potential strategy for the treatment of gastric cancer. Herein, we found that the methylation status of the RB1 promoter was negatively related to the development of gastric tumors, while its expression was positively correlated with TET2 and TET3 expression. Further reactivation of RB1 expression by curcumin could inhibit gastric cell viability and carcinogenesis both in vitro and in vivo. Molecular docking and other studies confirmed that curcumin could bind to and upregulate the expression of TET2 and TET3 with hydrogen bonds and arene-H bonds, suggesting that demethylation of RB1 was attributed to reactivation of the demethylation enzymes TET2 and TET3 after curcumin treatment. Thus, our findings reveal a promising therapeutic strategy for gastric cancer prevention and treatment through RB1 demethylation and reactivation.
AB - Aberrant methylation of promoter CpG islands (CGIs) can inactivate the expression of many tumor suppressor genes and play an important role in the carcinogenesis of gastric cancer. The tumor suppressor gene RB1, which encodes a cell cycle regulator, is hypermethylated and downregulated in multiple kinds of cancer. Activation of RB1 expression through DNA demethylation is a potential strategy for the treatment of gastric cancer. Herein, we found that the methylation status of the RB1 promoter was negatively related to the development of gastric tumors, while its expression was positively correlated with TET2 and TET3 expression. Further reactivation of RB1 expression by curcumin could inhibit gastric cell viability and carcinogenesis both in vitro and in vivo. Molecular docking and other studies confirmed that curcumin could bind to and upregulate the expression of TET2 and TET3 with hydrogen bonds and arene-H bonds, suggesting that demethylation of RB1 was attributed to reactivation of the demethylation enzymes TET2 and TET3 after curcumin treatment. Thus, our findings reveal a promising therapeutic strategy for gastric cancer prevention and treatment through RB1 demethylation and reactivation.
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U2 - 10.1016/j.lfs.2020.118580
DO - 10.1016/j.lfs.2020.118580
M3 - Article
C2 - 33058920
AN - SCOPUS:85092722726
SN - 0024-3205
VL - 263
JO - Life Sciences
JF - Life Sciences
M1 - 118580
ER -