DNMT1 inhibition reprograms pancreatic cancer stem cells via upregulation of the miR-17-92 cluster

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dc.contributor.author Zagorac, Sladjana
dc.contributor.author Alcala, Sonia
dc.contributor.author Bayon, G.F.
dc.contributor.author Kheir, Tony Bou
dc.contributor.author Schoenhals, Matthieu
dc.contributor.author Gonzalez-Neira, Ana
dc.contributor.author Fernandez Fraga, Mario
dc.contributor.author Aicher, Alexandra
dc.contributor.author Heeschen, Christopher
dc.contributor.author Sainz, Bruno
dc.contributor.other UAM. Departamento de Bioquímica es_ES
dc.date.accessioned 2017-04-05T12:40:20Z
dc.date.available 2017-04-05T12:40:20Z
dc.date.issued 2016-08-01
dc.identifier.citation Cancer Research 76.15 (2016): 4546-4558 en_US
dc.identifier.issn 0008-5472 (print) en_US
dc.identifier.issn 1538-7445 (online) en_US
dc.identifier.uri http://hdl.handle.net/10486/677914
dc.description.abstract Pancreatic ductal adenocarcinoma (PDAC) and other carcinomas are hierarchically organized, with cancer stem cells (CSC) residing at the top of the hierarchy, where they drive tumor progression, metastasis, and chemoresistance. As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. In this study, we investigated the genome-wide DNA methylation profile of PDAC CSC, and we determined the importance of DNA methyltransferases for CSC maintenance and tumorigenicity. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. Mechanistically, CSC expressed higher DNMT1 levels than non-CSC. Pharmacologic or genetic targeting of DNMT1 in CSCs reduced their self-renewal and in vivo tumorigenic potential, defining DNMT1 as a candidate CSC therapeutic target. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR-17-92 cluster. Together, our findings indicate that DNA methylation plays an important role in CSC biology and also provide a rationale to develop epigenetic modulators to target CSC plasticity and improve the poor outcome of PDAC patients en_US
dc.description.sponsorship Research was supported by the ERC Advanced Investigator Grant (Pa-CSC 233460 to C. Heeschen) and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 256974 (EPC-TM-NET to C. Heeschen) and n° 602783 (CAM-PaC to C. Heeschen), the 2015 SU2C Lustgarten CRUK Pancreatic Cancer Dream Team Award (to C. Heeschen), Pancreatic Cancer UK RIF2014_04 and RIF2015_03 (both to C. Heeschen), a Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (to B. Sainz), a Clinic and Laboratory Integration Program (CLIP) grant from the Cancer Research Institute, NY, NY USA (to. B. Sainz) and a Proyecto de Investigación de Salud, ISCIII, Spain (n° PI15/01507 to B. Sainz) es_ES
dc.format.extent 55 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher Amer Assoc Cancer Research en_US
dc.relation.ispartof Cancer Research en_US
dc.rights © 2016 AACR es_ES
dc.subject.other PDAC en_US
dc.subject.other DNA methylation en_US
dc.subject.other DNMT1 en_US
dc.subject.other Zebularine en_US
dc.subject.other cancer stem cells en_US
dc.subject.other miR-17-92 en_US
dc.title DNMT1 inhibition reprograms pancreatic cancer stem cells via upregulation of the miR-17-92 cluster en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.date.embargoend 2017-08-01
dc.relation.publisherversion http://dx.doi.org/10.1158/0008-5472.CAN-15-3268 es_ES
dc.identifier.doi 10.1158/0008-5472.CAN-15-3268 es_ES
dc.identifier.publicationfirstpage 4546 es_ES
dc.identifier.publicationissue 15 es_ES
dc.identifier.publicationlastpage 4558 es_ES
dc.identifier.publicationvolume 76 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/233460 en
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/256974 en
dc.type.version info:eu-repo/semantics/acceptedVersion en
dc.rights.accessRights openAccess en
dc.authorUAM Sainz Anding, Bruno (264918)


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