机构：[1]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China,[2]School of Pharmaceutical Sciences, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China,[3]Department of Cardiac Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China,中山大学附属第一医院[4]National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, China,[5]Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China
Jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, specifically catalyzes the demethylation of H3K27 (H3K27me3) and regulates gene expression. Sestrin2 (SESN2), a stress-inducible protein, protected against doxorubicin (DOX)-induced cardiomyopathy by regulating mitophagy and mitochondrial function. Here, the expression of JMJD3 was increased and that of SESN2 was decreased in both the heart samples from patients with dilated cardiomyopathy and chronic DOX-stimulation induced cardiomyopathy. Inhibition or knockdown of JMJD3 attenuated DOX-induced cardiomyocytes apoptosis, mitochondrial injury and cardiac dysfunction. However, JMJD3 overexpression aggravated DOX-induced cardiomyopathy, which were relieved by SESN2 overexpression. JMJD3 inhibited the transcription of SESN2 by reducing tri-methylation of H3K27 in the promoter region of SESN2. In conclusion, JMJD3 negatively regulated SESN2 via decreasing H3K27me3 enrichment in the promoter region of SESN2, subsequently inducing mitochondrial dysfunction and cardiomyocytes apoptosis. Targeting the JMJD3-SESN2 signaling axis may be a potential therapeutic strategy to protect against DOX-mediated cardiomyopathy.
基金：
This research was supported by grants from the National
Natural Science Foundation of China (81872860, 81803521,
and 81673433), National Major Special Projects for the
Creation and Manufacture of New Drugs (2019ZX09301104),
Local Innovative and Research Teams Project of Guangdong
Pearl River Talents Program (2017BT01Y093), National
Engineering and Technology Research Center for New drug
Druggability Evaluation (Seed Program of Guangdong Province,
2017B090903004), Natural Science Foundation of Guangdong
Province (2019A1515010273), Foundation from Guangdong
Traditional Medicine Bureau (20191060), and Fundamental
Research Funds for the Central Universities (19ykpy131).
第一作者机构：[1]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China,
共同第一作者：
通讯作者：
通讯机构：[1]School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China,[4]National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou, China,[5]Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China
推荐引用方式(GB/T 7714)：
Panxia Wang,Rui Lan,Zhen Guo,et al.Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression[J].FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY.2020,8:doi:10.3389/fcell.2020.548605.
APA：
Panxia Wang,Rui Lan,Zhen Guo,Sidong Cai,Junjian Wang...&Peiqing Liu.(2020).Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY,8,
MLA：
Panxia Wang,et al."Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression".FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 8.(2020)
