Histone Demethylase JMJD3 Mediated Doxorubicin-Induced Cardiomyopathy by Suppressing SESN2 Expression.

Panxia Wang,Zhen Guo,Jingyan Li,Jing Lu,Zhenzhen Li,Qianqian Wang,Zhongkai Wu,Peiqing Liu,Quan Wang,Zeyu Li,Junjian Wang,Rui Lan,Sidong Cai

doi:10.3389/fcell.2020.548605

Abstract

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.

Highlights

Doxorubicin (DOX) is an effective broad-spectrum anthracycline antibiotic, which was commonly used in solid tumors and cancers since the late 1960 (Pacher et al, 2002; Li et al, 2006)
We demonstrated that the expression of histone demethylase Jumonji domain-containing 3 (JMJD3) were increased, while that of SESN2 were reduced in both human hearts with dilated cardiomyopathy and DOX-induced chronic cardiomyopathy model
The mRNA level of JMJD3 was increased in human heart tissues with dilated cardiomyopathy (DCM) (Figure 1A), while that of SESN2 was decreased (Figure 1B)

Summary

Introduction

Doxorubicin (DOX) is an effective broad-spectrum anthracycline antibiotic, which was commonly used in solid tumors and cancers (such as lung, breast, and severe leukemia) since the late 1960 (Pacher et al, 2002; Li et al, 2006). The lethal cardiotoxicity side effects of DOX limit its clinical application (Olson and Mushlin, 1990; Gao et al, 2014; Hosseini et al, 2017). By inducing mitochondrial dysfunction and increasing ROS accumulation, DOX could induce numerous cytopathological responses and even cardiomyocytes apoptosis (Wallace, 2007). DOX-induced cardiotoxicity is characterized by cardiac atrophy, cellular apoptosis, destruction of mitochondrial structure as well as depolarization of mitochondrial membrane (Hu et al, 2018). DOX treatment obviously activated apoptosis pathway of cardiomyocytes and induced ROS accumulation and cytochrome C release (Davies and Doroshow, 1986). Despite previous investigations (Gianni et al, 2008), the pathogenic mechanisms responsible for DOX-induced cardiomyopathy were not clear and need further exploration and the effects of drugs used to ameliorate cardiomyopathy were limited and unsatisfactory

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Conclusion