RNA m6A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO

Pujiao Yu; Jiaqi Wang; Gui-E Xu; Xuan Zhao; Xinxin Cui; Jingyi Feng; Jiangpeng Sun; Tianhui Wang; Michail Spanos; Helge Immo Lehmann; Guoping Li; Jiahong Xu; Lijun Wang; Junjie Xiao

doi:10.1016/j.jacbts.2022.12.005

RNA m⁶A-Regulated circ-ZNF609 Suppression Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating FTO

JACC Basic Transl Sci. 2023 Mar 1;8(6):677-698. doi: 10.1016/j.jacbts.2022.12.005. eCollection 2023 Jun.

Authors

Pujiao Yu^{1

2

3}, Jiaqi Wang^{1

4}, Gui-E Xu^{1

4}, Xuan Zhao^{1

4}, Xinxin Cui^{1

4}, Jingyi Feng^{1

4}, Jiangpeng Sun^{1

4}, Tianhui Wang^{1

4}, Michail Spanos⁵, Helge Immo Lehmann⁵, Guoping Li⁵, Jiahong Xu^{2

3}, Lijun Wang^{1

4}, Junjie Xiao^{1

4}

Affiliations

¹ Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, China.
² Department of Cardiology, Shanghai Pudong New Area Gongli Hospital, Shanghai, China.
³ Department of Cardiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, China.
⁵ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Cardiac death is a major burden for cancer survivors, yet there is currently no effective treatment for doxorubicin (DOX)-induced cardiotoxicity. Here, we report that circ-ZNF609 knockdown knockdown had cardioprotective effects against DOX-induced cardiomyocyte toxicity. Mechanistically, circ-ZNF609 knockdown alleviated DOX-induced cardiotoxicity through attenuating cardiomyocyte apoptosis, reducing reactive oxygen species production, ameliorating mitochondrial nonheme iron overload. circ-ZNF609 inhibition blocked the elevation of RNA N⁶-methyladenosine (RNA m⁶A) methylation level in DOX-treated mice hearts, whereas m⁶A demethylase fat mass and obesity associated (FTO) acted as the downstream factor of circ-ZNF609. Moreover, the stability of circ-ZNF609 was regulated by RNA m⁶A methylation alteration, and suppression of RNA m⁶A methylation by methyltransferase like 14 (METTL14) modulated the function of circ-ZNF609. These data suggest that circ-ZNF609 inhibition represents a potential therapy for DOX-induced cardiotoxicity.

Keywords: RNA N6-methyladenosine; cardiotoxicity; circ-ZNF609; circular RNA; doxorubicin-induced.