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Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells
The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line,...
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| Published in: | Molecular and cellular biology 2017-10, Vol.37 (22) |
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| Format: | Article |
| Language: | English |
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| container_title | Molecular and cellular biology |
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| creator | Iyer, Sucharitha Modali, Sita D. Agarwal, Sunita K. |
| description | The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using
ch
romatin
i
solation by
R
NA
p
urification and
seq
uencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes. |
| doi_str_mv | 10.1128/MCB.00278-17 |
| format | article |
| fullrecord | <record><control><sourceid>pubmedcentral</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5660463</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>pubmedcentral_primary_oai_pubmedcentral_nih_gov_5660463</sourcerecordid><originalsourceid>FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_56604633</originalsourceid><addsrcrecordid>eNqljMtOwzAQRS0Eoimw4wPmB1LsvLNBgpBCJRoQdB8ZZxqMknHkJEis-HVciQ1rVnd0z5zL2KXgKyGC7Gpb3K44D9LMF-kR8wTPMz-Oo_yYea7lfhryZMGW4_jBOU9yHp6yhftOAxFlHvt-NNRCZUiZRrvrpbqBbXkfwmYESVAOukXCSSu4wwltr0nSBGYPT85wyIFX3ZLsDrImWM-kJm1cAc-SlEV5cCucrUFqjLKaEHZzbywU2HXjOTvZy27Ei988Y9frclc8-MP81mOjkCYru3qwupf2qzZS138J6fe6NZ91nCQ8SsLw3wM_DpxtlQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells</title><source>PubMed Central</source><creator>Iyer, Sucharitha ; Modali, Sita D. ; Agarwal, Sunita K.</creator><creatorcontrib>Iyer, Sucharitha ; Modali, Sita D. ; Agarwal, Sunita K.</creatorcontrib><description>The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using
ch
romatin
i
solation by
R
NA
p
urification and
seq
uencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes.</description><identifier>ISSN: 0270-7306</identifier><identifier>EISSN: 1098-5549</identifier><identifier>DOI: 10.1128/MCB.00278-17</identifier><identifier>PMID: 27872148</identifier><identifier>PMID: 28847847</identifier><language>eng</language><publisher>1752 N St., N.W., Washington, DC: American Society for Microbiology</publisher><ispartof>Molecular and cellular biology, 2017-10, Vol.37 (22)</ispartof><rights>Copyright © 2017 American Society for Microbiology. 2017 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660463/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660463/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids></links><search><creatorcontrib>Iyer, Sucharitha</creatorcontrib><creatorcontrib>Modali, Sita D.</creatorcontrib><creatorcontrib>Agarwal, Sunita K.</creatorcontrib><title>Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells</title><title>Molecular and cellular biology</title><description>The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using
ch
romatin
i
solation by
R
NA
p
urification and
seq
uencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes.</description><issn>0270-7306</issn><issn>1098-5549</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqljMtOwzAQRS0Eoimw4wPmB1LsvLNBgpBCJRoQdB8ZZxqMknHkJEis-HVciQ1rVnd0z5zL2KXgKyGC7Gpb3K44D9LMF-kR8wTPMz-Oo_yYea7lfhryZMGW4_jBOU9yHp6yhftOAxFlHvt-NNRCZUiZRrvrpbqBbXkfwmYESVAOukXCSSu4wwltr0nSBGYPT85wyIFX3ZLsDrImWM-kJm1cAc-SlEV5cCucrUFqjLKaEHZzbywU2HXjOTvZy27Ei988Y9frclc8-MP81mOjkCYru3qwupf2qzZS138J6fe6NZ91nCQ8SsLw3wM_DpxtlQ</recordid><startdate>20171027</startdate><enddate>20171027</enddate><creator>Iyer, Sucharitha</creator><creator>Modali, Sita D.</creator><creator>Agarwal, Sunita K.</creator><general>American Society for Microbiology</general><scope>5PM</scope></search><sort><creationdate>20171027</creationdate><title>Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells</title><author>Iyer, Sucharitha ; Modali, Sita D. ; Agarwal, Sunita K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_56604633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iyer, Sucharitha</creatorcontrib><creatorcontrib>Modali, Sita D.</creatorcontrib><creatorcontrib>Agarwal, Sunita K.</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular and cellular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iyer, Sucharitha</au><au>Modali, Sita D.</au><au>Agarwal, Sunita K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells</atitle><jtitle>Molecular and cellular biology</jtitle><date>2017-10-27</date><risdate>2017</risdate><volume>37</volume><issue>22</issue><issn>0270-7306</issn><eissn>1098-5549</eissn><notes>Present address: Sita D. Modali, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.</notes><notes>Citation Iyer S, Modali SD, Agarwal SK. 2017. Long noncoding RNA MEG3 is an epigenetic determinant of oncogenic signaling in functional pancreatic neuroendocrine tumor cells. Mol Cell Biol 37:e00278-17. https://doi.org/10.1128/MCB.00278-17.</notes><abstract>The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using
ch
romatin
i
solation by
R
NA
p
urification and
seq
uencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet β-cell expansion through c-MET regulation to ameliorate β-cell loss in diabetes.</abstract><cop>1752 N St., N.W., Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>27872148</pmid><pmid>28847847</pmid><doi>10.1128/MCB.00278-17</doi></addata></record> |
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| title | Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells |
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