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De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy

Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinati...

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Published in:Experimental cell research 2021-09, Vol.406 (1), p.112761-112761, Article 112761
Main Authors: Lu, Peng, Xu, Yun, Sheng, Zhi-yong, Peng, Xiao-gang, Zhang, Jing-jing, Wu, Qing-hua, Wu, Yan-qing, Cheng, Xiao-shu, Zhu, Kai
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container_title Experimental cell research
container_volume 406
creator Lu, Peng
Xu, Yun
Sheng, Zhi-yong
Peng, Xiao-gang
Zhang, Jing-jing
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Wu, Yan-qing
Cheng, Xiao-shu
Zhu, Kai
description Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy. Proposed model of Deubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced Cardiac Hypertrophy. In this study, we demonstrated that Ang II treatment induced the expression of USP12, thereby increasing the interaction between USP12 and histone acetyltransferase p300. USP12 deubiquitinated the ubiquitination modification of p300 to block its degradation and increase p300 expression, thus promoting the transcription of METTL3 to aggravate Ang II-induced cardiomyocyte hypertrophy. [Display omitted] •The expression of USP12 is increased in Ang II-induced cardiac hypertrophy in vitro and in vivo.•USP1
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The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy. Proposed model of Deubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced Cardiac Hypertrophy. In this study, we demonstrated that Ang II treatment induced the expression of USP12, thereby increasing the interaction between USP12 and histone acetyltransferase p300. USP12 deubiquitinated the ubiquitination modification of p300 to block its degradation and increase p300 expression, thus promoting the transcription of METTL3 to aggravate Ang II-induced cardiomyocyte hypertrophy. [Display omitted] •The expression of USP12 is increased in Ang II-induced cardiac hypertrophy in vitro and in vivo.•USP12 aggravates Ang II-induced cardiomyocyte hypertrophy via upregulating METTL3.•USP12 promoted METTL3 expression via modulating p300.•USP12 suppresses the ubiquitination of p300 to block its degradation.</description><identifier>ISSN: 0014-4827</identifier><identifier>EISSN: 1090-2422</identifier><identifier>DOI: 10.1016/j.yexcr.2021.112761</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Deubiquitinating enzyme ; HEART ; HEART FAILURE ; HOMEOSTASIS ; HYPERTROPHY ; IN VITRO ; IN VIVO ; INHIBITION ; MESSENGER-RNA ; METHYL TRANSFERASES ; METTL3 ; p300 ; Pathological cardiac hypertrophy ; PHENOTYPE ; RATS ; TRANSCRIPTION ; USP12</subject><ispartof>Experimental cell research, 2021-09, Vol.406 (1), p.112761-112761, Article 112761</ispartof><rights>2021 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-5958a6e5d4c82f5dcec3be38e22460da705984be61511f6f9ae985f400b65b683</citedby><cites>FETCH-LOGICAL-c430t-5958a6e5d4c82f5dcec3be38e22460da705984be61511f6f9ae985f400b65b683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.osti.gov/biblio/23195533$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Peng</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Sheng, Zhi-yong</creatorcontrib><creatorcontrib>Peng, Xiao-gang</creatorcontrib><creatorcontrib>Zhang, Jing-jing</creatorcontrib><creatorcontrib>Wu, Qing-hua</creatorcontrib><creatorcontrib>Wu, Yan-qing</creatorcontrib><creatorcontrib>Cheng, Xiao-shu</creatorcontrib><creatorcontrib>Zhu, Kai</creatorcontrib><title>De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy</title><title>Experimental cell research</title><description>Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy. Proposed model of Deubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced Cardiac Hypertrophy. In this study, we demonstrated that Ang II treatment induced the expression of USP12, thereby increasing the interaction between USP12 and histone acetyltransferase p300. USP12 deubiquitinated the ubiquitination modification of p300 to block its degradation and increase p300 expression, thus promoting the transcription of METTL3 to aggravate Ang II-induced cardiomyocyte hypertrophy. [Display omitted] •The expression of USP12 is increased in Ang II-induced cardiac hypertrophy in vitro and in vivo.•USP12 aggravates Ang II-induced cardiomyocyte hypertrophy via upregulating METTL3.•USP12 promoted METTL3 expression via modulating p300.•USP12 suppresses the ubiquitination of p300 to block its degradation.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Deubiquitinating enzyme</subject><subject>HEART</subject><subject>HEART FAILURE</subject><subject>HOMEOSTASIS</subject><subject>HYPERTROPHY</subject><subject>IN VITRO</subject><subject>IN VIVO</subject><subject>INHIBITION</subject><subject>MESSENGER-RNA</subject><subject>METHYL TRANSFERASES</subject><subject>METTL3</subject><subject>p300</subject><subject>Pathological cardiac hypertrophy</subject><subject>PHENOTYPE</subject><subject>RATS</subject><subject>TRANSCRIPTION</subject><subject>USP12</subject><issn>0014-4827</issn><issn>1090-2422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kcGO0zAQhi0EEmXhCbhY4sIl3bEdu8mBw6oUtlIRSHTPlmNPqKusnbUTtHl7EsKZ0xzm_0Yz8xHynsGWAVO31-2EzzZtOXC2ZYzvFHtBNgxqKHjJ-UuyAWBlUVZ895q8yfkKAFXF1IbEz1iMjX8a_eCDGXwMNLa0FwC0mejDzx-M032am9Z03UQP4WKCxUy_Hc7nk6CH5z5hzgtmgqN34Rc9Hgsf3GjRUWuS88bSy9RjGlLsL9Nb8qo1XcZ3_-oNefhyOO_vi9P3r8f93amwpYChkLWsjELpSlvxVjqLVjQoKuS8VODMDmRdlQ0qJhlrVVsbrCvZlgCNko2qxA35sM6NefA6Wz-gvdgYAtpBc8FqKYWYUx_XVJ_i04h50I8-W-w6EzCOWXMpd1KomvE5KtaoTTHnhK3uk380adIM9CJBX_VfCXqRoFcJM_VppXC-9bfHtKyC8wedT8smLvr_8n8ANsSPSw</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Lu, Peng</creator><creator>Xu, Yun</creator><creator>Sheng, Zhi-yong</creator><creator>Peng, Xiao-gang</creator><creator>Zhang, Jing-jing</creator><creator>Wu, Qing-hua</creator><creator>Wu, Yan-qing</creator><creator>Cheng, Xiao-shu</creator><creator>Zhu, Kai</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20210901</creationdate><title>De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy</title><author>Lu, Peng ; Xu, Yun ; Sheng, Zhi-yong ; Peng, Xiao-gang ; Zhang, Jing-jing ; Wu, Qing-hua ; Wu, Yan-qing ; Cheng, Xiao-shu ; Zhu, Kai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-5958a6e5d4c82f5dcec3be38e22460da705984be61511f6f9ae985f400b65b683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Deubiquitinating enzyme</topic><topic>HEART</topic><topic>HEART FAILURE</topic><topic>HOMEOSTASIS</topic><topic>HYPERTROPHY</topic><topic>IN VITRO</topic><topic>IN VIVO</topic><topic>INHIBITION</topic><topic>MESSENGER-RNA</topic><topic>METHYL TRANSFERASES</topic><topic>METTL3</topic><topic>p300</topic><topic>Pathological cardiac hypertrophy</topic><topic>PHENOTYPE</topic><topic>RATS</topic><topic>TRANSCRIPTION</topic><topic>USP12</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Peng</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Sheng, Zhi-yong</creatorcontrib><creatorcontrib>Peng, Xiao-gang</creatorcontrib><creatorcontrib>Zhang, Jing-jing</creatorcontrib><creatorcontrib>Wu, Qing-hua</creatorcontrib><creatorcontrib>Wu, Yan-qing</creatorcontrib><creatorcontrib>Cheng, Xiao-shu</creatorcontrib><creatorcontrib>Zhu, Kai</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Experimental cell research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Peng</au><au>Xu, Yun</au><au>Sheng, Zhi-yong</au><au>Peng, Xiao-gang</au><au>Zhang, Jing-jing</au><au>Wu, Qing-hua</au><au>Wu, Yan-qing</au><au>Cheng, Xiao-shu</au><au>Zhu, Kai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy</atitle><jtitle>Experimental cell research</jtitle><date>2021-09-01</date><risdate>2021</risdate><volume>406</volume><issue>1</issue><spage>112761</spage><epage>112761</epage><pages>112761-112761</pages><artnum>112761</artnum><issn>0014-4827</issn><eissn>1090-2422</eissn><abstract>Stresses, such as neurohumoral activation, induced pathological cardiac hypertrophy is the main risk factor for heart failure. The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role and mechanism of deubiquitinating enzymes (DUBs) in cardiac hypertrophy is limited. Here, we observe that the deubiquitinating enzyme ubiquitin-specific protease 12(USP12) is upregulated in Ang II-induced hypertrophic hearts and primary neonatal rat cardiomyocytes (NRCMs). Inhibition of USP12 ameliorate Ang II-induced myocardial hypertrophy, while overexpression of USP12 have the opposite effect. USP12 deficiency also significantly attenuate the phenotype of Ang II-induced cardiac hypertrophy in vivo. Moreover, we demonstrate that USP12 aggravate Ang II-induced cardiac hypertrophy by enhancing METTL3, a methyltransferase which catalyze N6-methyladenosine (m6A) modification on messenger RNA and acts as a harmful factor in pathological cardiac hypertrophy. Upregulation of METTL3 reverse the reduction of myocardial hypertrophy induced by USP12 silencing in NRCMs. In contrast, knockdown of METTL3 attenuate the aggravation of myocardial hypertrophy in USP12-overexpressing NRCMs. Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300. Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3. Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy. Taken together, our results demonstrate that USP12 acts as a pro-hypertrophic deubiquitinating enzyme via enhancing p300/METTL3 axis, indicating that targeting USP12 could be a potential treatment strategy for pathological cardiac hypertrophy. Proposed model of Deubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced Cardiac Hypertrophy. In this study, we demonstrated that Ang II treatment induced the expression of USP12, thereby increasing the interaction between USP12 and histone acetyltransferase p300. USP12 deubiquitinated the ubiquitination modification of p300 to block its degradation and increase p300 expression, thus promoting the transcription of METTL3 to aggravate Ang II-induced cardiomyocyte hypertrophy. [Display omitted] •The expression of USP12 is increased in Ang II-induced cardiac hypertrophy in vitro and in vivo.•USP12 aggravates Ang II-induced cardiomyocyte hypertrophy via upregulating METTL3.•USP12 promoted METTL3 expression via modulating p300.•USP12 suppresses the ubiquitination of p300 to block its degradation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><doi>10.1016/j.yexcr.2021.112761</doi><tpages>1</tpages></addata></record>
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identifier ISSN: 0014-4827
ispartof Experimental cell research, 2021-09, Vol.406 (1), p.112761-112761, Article 112761
issn 0014-4827
1090-2422
language eng
recordid cdi_osti_scitechconnect_23195533
source ScienceDirect Freedom Collection
subjects 60 APPLIED LIFE SCIENCES
Deubiquitinating enzyme
HEART
HEART FAILURE
HOMEOSTASIS
HYPERTROPHY
IN VITRO
IN VIVO
INHIBITION
MESSENGER-RNA
METHYL TRANSFERASES
METTL3
p300
Pathological cardiac hypertrophy
PHENOTYPE
RATS
TRANSCRIPTION
USP12
title De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced cardiac hypertrophy
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