PMID- 37871668 OWN - NLM STAT- MEDLINE DCOM- 20231204 LR - 20240322 IS - 1873-3913 (Electronic) IS - 0898-6568 (Linking) VI - 113 DP - 2024 Jan TI - Deubiquitinase OTUB1 regulates doxorubicin-induced cardiotoxicity via deubiquitinating c-MYC. PG - 110937 LID - S0898-6568(23)00352-2 [pii] LID - 10.1016/j.cellsig.2023.110937 [doi] AB - BACKGROUND: Doxorubicin (DOX), an anthracycline drug widely used in antitumor therapies, has dose-dependent toxicity that can cause cardiomyocyte apoptosis and oxidative stress, thus limiting its clinical application. OTUB1 (ovarian tumor associated proteinase B1) is an OTU superfamily deubiquitinase that effectively regulates cell proliferation, inflammatory responses, apoptosis, and oxidative stress by specifically removing K48- and K63-linked ubiquitination; however, its role in DOX-induced cardiotoxicity remains unknown. MATERIALS AND METHODS: A DOX-induced subacute cardiotoxicity mouse model was established by intraperitoneal injection, and cardiac injury was assessed by echocardiography, serum cardiac markers, and histopathological staining. Western blotting, qRT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) immunohistochemistry were used to analyze cell apoptosis, tissue oxidative stress was assessed by superoxide dismutase (SOD) activity, malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) activity. Cell counting kit-8 (CCK-8) assay, TUNEL staining, Western blotting, qRT-PCR, and reactive oxygen species (ROS) flow cytometry were applied on isolated neonatal mice cardiomyocytes to assess apoptosis and oxidative stress. Differentially expressed genes were analyzed using RNA sequencing and clustering analyses. c-MYC inhibitor 10,058-F4 and siRNA targeting c-Myc were used to investigate the roles of c-MYC in OTUB1's regulations of DOX-induced cardiotoxicity. Immunoprecipitation and Western blotting were performed to reveal the deubiquitinating effects of OTUB1 on c-MYC expression. RESULTS: We found that global Otub1-knockdown in vivo alleviated the subacute DOX treatment-induced cardiac dysfunction, fibrosis, and cardiomyocyte atrophy. Mechanistically, unbiased RNA sequencing and molecular biology experiments revealed that cardiomyocyte apoptosis, inflammation, and oxidative stress in DOX-induced cardiotoxicity were significantly compromised in the Otub1-knockdown group. Further in vitro studies have shown that c-MYC, a critical regulator of apoptosis, is indispensable in OTUB1's regulations of DOX-induced cardiotoxicity. Deubiquitinating effects of OTUB1 on K48- and K63-linked ubiquitination of c-MYC protein are essential for promoting cardiomyocyte apoptosis and oxidative responses. CONCLUSIONS: OTUB1-c-MYC inhibition protected cardiomyocytes against DOX-induced apoptosis and oxidative stress, suggesting that OTUB1 is a potential translational therapeutic target for preventing DOX-induced cardiotoxicity. CI - Copyright (c) 2023. Published by Elsevier Inc. FAU - Xu, Fei AU - Xu F AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China; Department of Cardiology and Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China. FAU - Zang, Tongtong AU - Zang T AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. FAU - Chen, Han AU - Chen H AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. FAU - Zhou, Changyi AU - Zhou C AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. FAU - Wang, Rui AU - Wang R AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. FAU - Yu, Yue AU - Yu Y AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. FAU - Shen, Li AU - Shen L AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. Electronic address: shen.li1@zs-hospital.sh.cn. FAU - Qian, Juying AU - Qian J AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. Electronic address: qian.juying@zs-hospital.sh.cn. FAU - Ge, Junbo AU - Ge J AD - Department of Cardiology, Zhongshan Hospital, Fudan University, Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), Shanghai, China. Electronic address: ge.junbo2@zs-hospital.sh.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20231021 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 80168379AG (Doxorubicin) RN - 0 (Antioxidants) RN - EC 3.4.19.12 (Deubiquitinating Enzymes) SB - IM MH - Mice MH - Animals MH - *Cardiotoxicity/metabolism MH - *Doxorubicin/toxicity MH - Myocytes, Cardiac/metabolism MH - Oxidative Stress MH - Apoptosis MH - Antioxidants/pharmacology MH - Deubiquitinating Enzymes/metabolism OTO - NOTNLM OT - Cardiotoxicity OT - Deubiquitinase OT - Doxorubicin OT - Heart failure OT - OTUB1 COIS- Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Junbo Ge reports financial support was provided by National Key Research and Development Program of China. Li Shen reports financial support was provided by National Natural Science Foundation of China. Junbo Ge reports financial support was provided by Shanghai Engineering Research Center of Interventional Medicine. Juying Qian reports financial support was provided by Shanghai Clinical Research Center for Interventional Medicine. EDAT- 2023/10/24 00:41 MHDA- 2023/12/04 12:42 CRDT- 2023/10/23 19:27 PHST- 2023/07/06 00:00 [received] PHST- 2023/10/04 00:00 [revised] PHST- 2023/10/19 00:00 [accepted] PHST- 2023/12/04 12:42 [medline] PHST- 2023/10/24 00:41 [pubmed] PHST- 2023/10/23 19:27 [entrez] AID - S0898-6568(23)00352-2 [pii] AID - 10.1016/j.cellsig.2023.110937 [doi] PST - ppublish SO - Cell Signal. 2024 Jan;113:110937. doi: 10.1016/j.cellsig.2023.110937. Epub 2023 Oct 21.