Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss
Abstract The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In...
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| Veröffentlicht in: | Neurobiology of aging 2015-04, Vol.36 (4), p.1692-1701 |
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| creator | Xiong, Hao Pang, Jiaqi Yang, Haidi Dai, Min Liu, Yimin Ou, Yongkang Huang, Qiuhong Chen, Suijun Zhang, Zhigang Xu, Yaodong Lai, Lan Zheng, Yiqing |
| description | Abstract The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment. |
| doi_str_mv | 10.1016/j.neurobiolaging.2014.12.034 |
| format | Article |
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MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2014.12.034</identifier><identifier>PMID: 25638533</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acetylation ; Aging ; Animals ; Apoptosis - drug effects ; Apoptosis - genetics ; Cell Line ; Cochlea ; Gene Expression ; Hair Cells, Auditory - pathology ; Hearing Loss, Sensorineural - drug therapy ; Hearing Loss, Sensorineural - pathology ; Internal Medicine ; Mice, Inbred C57BL ; MicroRNA ; MicroRNAs - physiology ; Neurology ; p53 ; Presbycusis ; Signal Transduction - drug effects ; Signal Transduction - physiology ; SIRT1 ; Sirtuin 1 - metabolism ; Sirtuin 1 - physiology ; Stilbenes - administration & dosage ; Stilbenes - pharmacology ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Protein p53 - physiology</subject><ispartof>Neurobiology of aging, 2015-04, Vol.36 (4), p.1692-1701</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c577t-eafe8abe2dd7f277a4b2e7cc0fdd7d96bd830d916686c19f1e126e32895cfc1f3</citedby><cites>FETCH-LOGICAL-c577t-eafe8abe2dd7f277a4b2e7cc0fdd7d96bd830d916686c19f1e126e32895cfc1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.neurobiolaging.2014.12.034$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3541,27915,27916,45986</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25638533$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xiong, Hao</creatorcontrib><creatorcontrib>Pang, Jiaqi</creatorcontrib><creatorcontrib>Yang, Haidi</creatorcontrib><creatorcontrib>Dai, Min</creatorcontrib><creatorcontrib>Liu, Yimin</creatorcontrib><creatorcontrib>Ou, Yongkang</creatorcontrib><creatorcontrib>Huang, Qiuhong</creatorcontrib><creatorcontrib>Chen, Suijun</creatorcontrib><creatorcontrib>Zhang, Zhigang</creatorcontrib><creatorcontrib>Xu, Yaodong</creatorcontrib><creatorcontrib>Lai, Lan</creatorcontrib><creatorcontrib>Zheng, Yiqing</creatorcontrib><title>Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment.</description><subject>Acetylation</subject><subject>Aging</subject><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Cell Line</subject><subject>Cochlea</subject><subject>Gene Expression</subject><subject>Hair Cells, Auditory - pathology</subject><subject>Hearing Loss, Sensorineural - drug therapy</subject><subject>Hearing Loss, Sensorineural - pathology</subject><subject>Internal Medicine</subject><subject>Mice, Inbred C57BL</subject><subject>MicroRNA</subject><subject>MicroRNAs - physiology</subject><subject>Neurology</subject><subject>p53</subject><subject>Presbycusis</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>SIRT1</subject><subject>Sirtuin 1 - metabolism</subject><subject>Sirtuin 1 - physiology</subject><subject>Stilbenes - administration & dosage</subject><subject>Stilbenes - pharmacology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Protein p53 - physiology</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUk1v1DAQtRCILoW_gHzgwCVZO45jByGkqqJQqRJSW86W44x3vThxsJNKvfHTcdhSqZw4WWO9j5l5g9A7SkpKaLM9lCMsMXQueL1z466sCK1LWpWE1c_QhnIuC1q34jnaENqKouaSnKBXKR0IIaIWzUt0UvGGSc7YBv06M7O707MLIw4WD-66YLXe3lxe39LtxBlObjdqn32wCeMcXbfMkPAccmn2HnTEe-0iNuA91lOY5pBc-oDdMHln_ugmbEPEegdFBK9n6PE-01ZFH1J6jV5Y7RO8eXhP0feLz7fnX4urb18uz8-uCsOFmAvQFqTuoOp7YSshdN1VIIwhNn_0bdP1kpG-pU0jG0NbS4FWDbBKttxYQy07Re-PulMMPxdIsxpcWrvWI4QlqcwUrJZcygz9eISamBuMYNUU3aDjvaJErRmog3qagVozULRSOYNMf_vgtHQD9I_kv0vPgIsjAPK8dw6iSsbBaKB3Ecys-uD-1-nTP0ImJ5XX7n_APaRDWGLOLs-mUiaom_Ue1nOgNSGSU8Z-A24YuA4</recordid><startdate>20150401</startdate><enddate>20150401</enddate><creator>Xiong, Hao</creator><creator>Pang, Jiaqi</creator><creator>Yang, Haidi</creator><creator>Dai, Min</creator><creator>Liu, Yimin</creator><creator>Ou, Yongkang</creator><creator>Huang, Qiuhong</creator><creator>Chen, Suijun</creator><creator>Zhang, Zhigang</creator><creator>Xu, Yaodong</creator><creator>Lai, Lan</creator><creator>Zheng, Yiqing</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150401</creationdate><title>Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss</title><author>Xiong, Hao ; Pang, Jiaqi ; Yang, Haidi ; Dai, Min ; Liu, Yimin ; Ou, Yongkang ; Huang, Qiuhong ; Chen, Suijun ; Zhang, Zhigang ; Xu, Yaodong ; Lai, Lan ; Zheng, Yiqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c577t-eafe8abe2dd7f277a4b2e7cc0fdd7d96bd830d916686c19f1e126e32895cfc1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acetylation</topic><topic>Aging</topic><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Cell Line</topic><topic>Cochlea</topic><topic>Gene Expression</topic><topic>Hair Cells, Auditory - pathology</topic><topic>Hearing Loss, Sensorineural - drug therapy</topic><topic>Hearing Loss, Sensorineural - pathology</topic><topic>Internal Medicine</topic><topic>Mice, Inbred C57BL</topic><topic>MicroRNA</topic><topic>MicroRNAs - physiology</topic><topic>Neurology</topic><topic>p53</topic><topic>Presbycusis</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>SIRT1</topic><topic>Sirtuin 1 - metabolism</topic><topic>Sirtuin 1 - physiology</topic><topic>Stilbenes - administration & dosage</topic><topic>Stilbenes - pharmacology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Protein p53 - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xiong, Hao</creatorcontrib><creatorcontrib>Pang, Jiaqi</creatorcontrib><creatorcontrib>Yang, Haidi</creatorcontrib><creatorcontrib>Dai, Min</creatorcontrib><creatorcontrib>Liu, Yimin</creatorcontrib><creatorcontrib>Ou, Yongkang</creatorcontrib><creatorcontrib>Huang, Qiuhong</creatorcontrib><creatorcontrib>Chen, Suijun</creatorcontrib><creatorcontrib>Zhang, Zhigang</creatorcontrib><creatorcontrib>Xu, Yaodong</creatorcontrib><creatorcontrib>Lai, Lan</creatorcontrib><creatorcontrib>Zheng, Yiqing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xiong, Hao</au><au>Pang, Jiaqi</au><au>Yang, Haidi</au><au>Dai, Min</au><au>Liu, Yimin</au><au>Ou, Yongkang</au><au>Huang, Qiuhong</au><au>Chen, Suijun</au><au>Zhang, Zhigang</au><au>Xu, Yaodong</au><au>Lai, Lan</au><au>Zheng, Yiqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>36</volume><issue>4</issue><spage>1692</spage><epage>1701</epage><pages>1692-1701</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><abstract>Abstract The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25638533</pmid><doi>10.1016/j.neurobiolaging.2014.12.034</doi><tpages>10</tpages></addata></record> |
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| subjects | Acetylation Aging Animals Apoptosis - drug effects Apoptosis - genetics Cell Line Cochlea Gene Expression Hair Cells, Auditory - pathology Hearing Loss, Sensorineural - drug therapy Hearing Loss, Sensorineural - pathology Internal Medicine Mice, Inbred C57BL MicroRNA MicroRNAs - physiology Neurology p53 Presbycusis Signal Transduction - drug effects Signal Transduction - physiology SIRT1 Sirtuin 1 - metabolism Sirtuin 1 - physiology Stilbenes - administration & dosage Stilbenes - pharmacology Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Protein p53 - physiology |
| title | Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss |
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