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Article: miR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer

TitlemiR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer
Authors
Issue Date2019
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2019, v. 38 n. 4, p. 564-580 How to Cite?
AbstractPlatinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.
Persistent Identifierhttp://hdl.handle.net/10722/260637
ISSN
2017 Impact Factor: 6.854
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSun, J-
dc.contributor.authorCai, X-
dc.contributor.authorYung, MMH-
dc.contributor.authorZhou, W-
dc.contributor.authorLi, J-
dc.contributor.authorZhang, Y-
dc.contributor.authorLi, Z-
dc.contributor.authorLiu, SS-
dc.contributor.authorCheung, ANY-
dc.contributor.authorNgan, HYS-
dc.contributor.authorLi, Y-
dc.contributor.authorDai, Z-
dc.contributor.authorKai, Y-
dc.contributor.authorTzatsos, A-
dc.contributor.authorPeng, W-
dc.contributor.authorChan, DW-
dc.contributor.authorZhu, W-
dc.date.accessioned2018-09-14T08:44:53Z-
dc.date.available2018-09-14T08:44:53Z-
dc.date.issued2019-
dc.identifier.citationOncogene, 2019, v. 38 n. 4, p. 564-580-
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/260637-
dc.description.abstractPlatinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogene-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in Oncogene. The final authenticated version is available online at: https://doi.org/10.1038/s41388-018-0459-x-
dc.titlemiR-137 mediates the functional link between c-Myc and EZH2 that regulates cisplatin resistance in ovarian cancer-
dc.typeArticle-
dc.identifier.emailYung, MMH: mhyung@hku.hk-
dc.identifier.emailLiu, SS: stephasl@hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.emailChan, DW: dwchan@hku.hk-
dc.identifier.authorityLiu, SS=rp00372-
dc.identifier.authorityCheung, ANY=rp00542-
dc.identifier.authorityNgan, HYS=rp00346-
dc.identifier.authorityChan, DW=rp00543-
dc.description.naturepostprint-
dc.identifier.doi10.1038/s41388-018-0459-x-
dc.identifier.pmid30166592-
dc.identifier.scopuseid_2-s2.0-85053031912-
dc.identifier.hkuros290017-
dc.identifier.hkuros298769-
dc.identifier.volume38-
dc.identifier.issue4-
dc.identifier.spage564-
dc.identifier.epage580-
dc.identifier.isiWOS:000456589800008-
dc.publisher.placeUnited Kingdom-

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