Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression
The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether micro...
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description | The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor–induced miR-663 expression by N-acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti–miR-663 reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in vivo in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis. |
doi_str_mv | 10.1074/jbc.M117.797001 |
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Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor–induced miR-663 expression by N-acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti–miR-663 reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in vivo in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M117.797001</identifier><identifier>PMID: 29066618</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; breast cancer ; Breast Neoplasms - enzymology ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line, Tumor ; Cell Nucleus - drug effects ; Cell Nucleus - metabolism ; Cell Nucleus - pathology ; DNA methylation ; DNA, Mitochondrial - metabolism ; Enzyme Inhibitors - pharmacology ; Epigenesis, Genetic - drug effects ; Female ; Gene Deletion ; gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulation ; Humans ; Mice, Nude ; microRNA (miRNA) ; MicroRNAs - antagonists & inhibitors ; MicroRNAs - metabolism ; miR-663 ; mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - pathology ; Neoplasm Transplantation ; Oxidative Phosphorylation - drug effects ; Oxidative Stress - drug effects ; OXPHOS ; retrograde signaling ; RNA - metabolism ; RNA, Neoplasm - antagonists & inhibitors ; RNA, Neoplasm - metabolism ; Signal Transduction - drug effects ; Tumor Burden ; tumorigenesis</subject><ispartof>The Journal of biological chemistry, 2017-12, Vol.292 (50), p.20694-20706</ispartof><rights>2017 © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-7f6d3b93ea15beb738cc8bf948cc35a43abc1a3e2f013833984ebcb01be928703</citedby><cites>FETCH-LOGICAL-c439t-7f6d3b93ea15beb738cc8bf948cc35a43abc1a3e2f013833984ebcb01be928703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733605/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733605/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29066618$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carden, Trevor</creatorcontrib><creatorcontrib>Singh, Bhupendra</creatorcontrib><creatorcontrib>Mooga, Ved</creatorcontrib><creatorcontrib>Bajpai, Prachi</creatorcontrib><creatorcontrib>Singh, Keshav K.</creatorcontrib><title>Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor–induced miR-663 expression by N-acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti–miR-663 reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in vivo in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.</description><subject>Animals</subject><subject>breast cancer</subject><subject>Breast Neoplasms - enzymology</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Nucleus - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell Nucleus - pathology</subject><subject>DNA methylation</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulation</subject><subject>Humans</subject><subject>Mice, Nude</subject><subject>microRNA (miRNA)</subject><subject>MicroRNAs - antagonists & inhibitors</subject><subject>MicroRNAs - metabolism</subject><subject>miR-663</subject><subject>mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Neoplasm Transplantation</subject><subject>Oxidative Phosphorylation - drug effects</subject><subject>Oxidative Stress - drug effects</subject><subject>OXPHOS</subject><subject>retrograde signaling</subject><subject>RNA - metabolism</subject><subject>RNA, Neoplasm - antagonists & inhibitors</subject><subject>RNA, Neoplasm - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Tumor Burden</subject><subject>tumorigenesis</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1LAzEQhoMotlbP3iR_YNtks1-5CFLqB1QEUfAWkuzsNmU3Kcm24L83pVr04FwG5n3nGeZF6JqSKSVlNlsrPX2mtJyWvCSEnqAxJRVLWE4_TtGYkJQmPM2rEboIYU1iZZyeo1HKSVEUtBoju9iYFiwMRuPe1aYxWg7GWewa3JvXpCgY1s4O3nUhDganV87W3shkcInd6g62AXuIeutlDTiY1srO2BZLW-Nh2zuPN3sRQojYS3TWyC7A1XefoPf7xdv8MVm-PDzN75aJzhgfkrIpaqY4A0lzBapkldaVangWO8tlxqTSVDJIG0JZxRivMlBaEaqAp1VJ2ATdHribreqh1hA_kJ3YeNNL_ymcNOKvYs1KtG4n8pKxguQRMDsAtHcheGiOu5SIffQiRi_20YtD9HHj5vfJo_8n62jgBwPEx3cGvAjagNVQGw96ELUz_8K_AA90l1Q</recordid><startdate>20171215</startdate><enddate>20171215</enddate><creator>Carden, Trevor</creator><creator>Singh, Bhupendra</creator><creator>Mooga, Ved</creator><creator>Bajpai, Prachi</creator><creator>Singh, Keshav K.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><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>5PM</scope></search><sort><creationdate>20171215</creationdate><title>Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression</title><author>Carden, Trevor ; Singh, Bhupendra ; Mooga, Ved ; Bajpai, Prachi ; Singh, Keshav K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-7f6d3b93ea15beb738cc8bf948cc35a43abc1a3e2f013833984ebcb01be928703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>breast cancer</topic><topic>Breast Neoplasms - enzymology</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Nucleus - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell Nucleus - pathology</topic><topic>DNA methylation</topic><topic>DNA, Mitochondrial - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Epigenesis, Genetic - drug effects</topic><topic>Female</topic><topic>Gene Deletion</topic><topic>gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulation</topic><topic>Humans</topic><topic>Mice, Nude</topic><topic>microRNA (miRNA)</topic><topic>MicroRNAs - antagonists & inhibitors</topic><topic>MicroRNAs - metabolism</topic><topic>miR-663</topic><topic>mitochondria</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Neoplasm Transplantation</topic><topic>Oxidative Phosphorylation - drug effects</topic><topic>Oxidative Stress - drug effects</topic><topic>OXPHOS</topic><topic>retrograde signaling</topic><topic>RNA - metabolism</topic><topic>RNA, Neoplasm - antagonists & inhibitors</topic><topic>RNA, Neoplasm - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Tumor Burden</topic><topic>tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carden, Trevor</creatorcontrib><creatorcontrib>Singh, Bhupendra</creatorcontrib><creatorcontrib>Mooga, Ved</creatorcontrib><creatorcontrib>Bajpai, Prachi</creatorcontrib><creatorcontrib>Singh, Keshav K.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carden, Trevor</au><au>Singh, Bhupendra</au><au>Mooga, Ved</au><au>Bajpai, Prachi</au><au>Singh, Keshav K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2017-12-15</date><risdate>2017</risdate><volume>292</volume><issue>50</issue><spage>20694</spage><epage>20706</epage><pages>20694-20706</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The normal cellular function requires communication between mitochondria and the nucleus, termed mitochondria-to-nucleus retrograde signaling. Disruption of this mechanism has been implicated in the development of cancers. Many proteins are known modulators of retrograde signaling, but whether microRNAs (miRNAs) are also involved is unknown. We conducted an miRNA microarray analysis using RNA from a parental cell line, a Rho0 line lacking mitochondrial DNA (mtDNA) and a Rho0 line with restored mtDNA. We found that miR-663 was down-regulated in the mtDNA-depleted Rho0 line. mtDNA restoration reversed this miRNA to parental level, suggesting that miR-663 may be epigenetically regulated by retrograde signaling. By using methylation-specific PCR and bisulfite sequencing we demonstrate that miR-663 promoter is epigenetically regulated not only by genetic but also by pharmacological disruption of oxidative phosphorylation (OXPHOS). Restoration of OXPHOS Complex I inhibitor–induced miR-663 expression by N-acetylcysteine suggested that reactive oxygen species (ROS) play a key role in epigenetic regulation of miR-663. We determined that miR-663 regulates the expression of nuclear-encoded respiratory chain subunits involved in Complexes I, II, III, and IV. miR-663 also controlled the expression of the Complexes I (NDUFAF1), II (SDHAF2), III (UQCC2), and IV (SCO1) assembly factors and was required for stability of respiratory supercomplexes. Furthermore, using luciferase assays, we found that miR-663 directly regulates UQCC2. The anti–miR-663 reduced OXPHOS complex activity and increased in vitro cellular proliferation and promoted tumor development in vivo in mice. We also found that increased miR-663 expression in breast tumors consistently correlates with increased patient survival. We provide the first evidence for miRNA controlling retrograde signaling, demonstrating its epigenetic regulation and its role in breast tumorigenesis.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29066618</pmid><doi>10.1074/jbc.M117.797001</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals breast cancer Breast Neoplasms - enzymology Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Cell Nucleus - drug effects Cell Nucleus - metabolism Cell Nucleus - pathology DNA methylation DNA, Mitochondrial - metabolism Enzyme Inhibitors - pharmacology Epigenesis, Genetic - drug effects Female Gene Deletion gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulation Humans Mice, Nude microRNA (miRNA) MicroRNAs - antagonists & inhibitors MicroRNAs - metabolism miR-663 mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Neoplasm Transplantation Oxidative Phosphorylation - drug effects Oxidative Stress - drug effects OXPHOS retrograde signaling RNA - metabolism RNA, Neoplasm - antagonists & inhibitors RNA, Neoplasm - metabolism Signal Transduction - drug effects Tumor Burden tumorigenesis |
title | Epigenetic modification of miR-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression |
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