Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Piqué, Laia; Martinez de Paz, A.; Piñeyro, David|||0000-0001-5633-3339; Martínez Cardús, Anna|||0000-0002-3937-8794; Castro de Moura, Manuel|||0000-0002-8488-5306; Llinàs-Arias, Pere|||0000-0002-3666-0532; Setien, F.; Gómez-Miragaya, Jorge|||0000-0003-1801-4681; González-Suárez, Eva|||0000-0003-0858-8171; Sigurdsson, S.|||0000-0002-5284-0058; Jonasson, J. G.; Villanueva, Alberto|||0000-0001-5164-0006; Vidal, A.; Davalos, Veronica|||0000-0003-4077-5137; Esteller, M.|||0000-0003-4490-6093

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost n...

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Autores:	Piqué, Laia, Martinez de Paz, A., Piñeyro, David\|\|\|0000-0001-5633-3339, Martínez Cardús, Anna\|\|\|0000-0002-3937-8794, Castro de Moura, Manuel\|\|\|0000-0002-8488-5306, Llinàs-Arias, Pere\|\|\|0000-0002-3666-0532, Setien, F., Gómez-Miragaya, Jorge\|\|\|0000-0003-1801-4681, González-Suárez, Eva\|\|\|0000-0003-0858-8171, Sigurdsson, S.\|\|\|0000-0002-5284-0058, Jonasson, J. G., Villanueva, Alberto\|\|\|0000-0001-5164-0006, Vidal, A., Davalos, Veronica\|\|\|0000-0003-4077-5137, Esteller, M.\|\|\|0000-0003-4490-6093
Tipo de recurso:	artículo
Fecha de publicación:	2019
País:	España
Institución:	Universitat Autònoma de Barcelona
Repositorio:	Dipòsit Digital de Documents de la UAB
Idioma:	inglés
OAI Identifier:	oai:ddd.uab.cat:236890
Acceso en línea:	https://ddd.uab.cat/record/236890 https://dx.doi.org/urn:doi:10.1038/s41388-019-0936-x
Access Level:	acceso abierto
Palabra clave:	Breast Neoplasms CELF Proteins DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans Nerve Tissue Proteins RNA Splicing Spliceosomes Tumor Cells, Cultured

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spelling	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancerPiqué, LaiaMartinez de Paz, A.Piñeyro, David\|\|\|0000-0001-5633-3339Martínez Cardús, Anna\|\|\|0000-0002-3937-8794Castro de Moura, Manuel\|\|\|0000-0002-8488-5306Llinàs-Arias, Pere\|\|\|0000-0002-3666-0532Setien, F.Gómez-Miragaya, Jorge\|\|\|0000-0003-1801-4681González-Suárez, Eva\|\|\|0000-0003-0858-8171Sigurdsson, S.\|\|\|0000-0002-5284-0058Jonasson, J. G.Villanueva, Alberto\|\|\|0000-0001-5164-0006Vidal, A.Davalos, Veronica\|\|\|0000-0003-4077-5137Esteller, M.\|\|\|0000-0003-4490-6093Breast NeoplasmsCELF ProteinsDNA MethylationEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticHumansNerve Tissue ProteinsRNA SplicingSpliceosomesTumor Cells, CulturedHuman tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.Universitat Autònoma de Barcelona 22019-01-0120192019-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/236890https://dx.doi.org/urn:doi:10.1038/s41388-019-0936-xreponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1080Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-633Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2009/SGR-1315Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 DTS16-00153Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-55000-Ropen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2368902026-06-06T12:50:31Z
dc.title.none.fl_str_mv	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
title	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
spellingShingle	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer Piqué, Laia Breast Neoplasms CELF Proteins DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans Nerve Tissue Proteins RNA Splicing Spliceosomes Tumor Cells, Cultured
title_short	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
title_full	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
title_fullStr	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
title_full_unstemmed	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
title_sort	Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer
dc.creator.none.fl_str_mv	Piqué, Laia Martinez de Paz, A. Piñeyro, David\|\|\|0000-0001-5633-3339 Martínez Cardús, Anna\|\|\|0000-0002-3937-8794 Castro de Moura, Manuel\|\|\|0000-0002-8488-5306 Llinàs-Arias, Pere\|\|\|0000-0002-3666-0532 Setien, F. Gómez-Miragaya, Jorge\|\|\|0000-0003-1801-4681 González-Suárez, Eva\|\|\|0000-0003-0858-8171 Sigurdsson, S.\|\|\|0000-0002-5284-0058 Jonasson, J. G. Villanueva, Alberto\|\|\|0000-0001-5164-0006 Vidal, A. Davalos, Veronica\|\|\|0000-0003-4077-5137 Esteller, M.\|\|\|0000-0003-4490-6093
author	Piqué, Laia
author_facet	Piqué, Laia Martinez de Paz, A. Piñeyro, David\|\|\|0000-0001-5633-3339 Martínez Cardús, Anna\|\|\|0000-0002-3937-8794 Castro de Moura, Manuel\|\|\|0000-0002-8488-5306 Llinàs-Arias, Pere\|\|\|0000-0002-3666-0532 Setien, F. Gómez-Miragaya, Jorge\|\|\|0000-0003-1801-4681 González-Suárez, Eva\|\|\|0000-0003-0858-8171 Sigurdsson, S.\|\|\|0000-0002-5284-0058 Jonasson, J. G. Villanueva, Alberto\|\|\|0000-0001-5164-0006 Vidal, A. Davalos, Veronica\|\|\|0000-0003-4077-5137 Esteller, M.\|\|\|0000-0003-4490-6093
author_role	author
author2	Martinez de Paz, A. Piñeyro, David\|\|\|0000-0001-5633-3339 Martínez Cardús, Anna\|\|\|0000-0002-3937-8794 Castro de Moura, Manuel\|\|\|0000-0002-8488-5306 Llinàs-Arias, Pere\|\|\|0000-0002-3666-0532 Setien, F. Gómez-Miragaya, Jorge\|\|\|0000-0003-1801-4681 González-Suárez, Eva\|\|\|0000-0003-0858-8171 Sigurdsson, S.\|\|\|0000-0002-5284-0058 Jonasson, J. G. Villanueva, Alberto\|\|\|0000-0001-5164-0006 Vidal, A. Davalos, Veronica\|\|\|0000-0003-4077-5137 Esteller, M.\|\|\|0000-0003-4490-6093
author2_role	author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv	Breast Neoplasms CELF Proteins DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans Nerve Tissue Proteins RNA Splicing Spliceosomes Tumor Cells, Cultured
topic	Breast Neoplasms CELF Proteins DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans Nerve Tissue Proteins RNA Splicing Spliceosomes Tumor Cells, Cultured
description	Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.
publishDate	2019
dc.date.none.fl_str_mv	2 2019-01-01 2019 2019-01-01
dc.type.none.fl_str_mv	Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://ddd.uab.cat/record/236890 https://dx.doi.org/urn:doi:10.1038/s41388-019-0936-x
url	https://ddd.uab.cat/record/236890 https://dx.doi.org/urn:doi:10.1038/s41388-019-0936-x
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.relation.none.fl_str_mv	Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1080 Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-633 Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2009/SGR-1315 Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 DTS16-00153 Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2014-55000-R
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:Dipòsit Digital de Documents de la UAB instname:Universitat Autònoma de Barcelona
instname_str	Universitat Autònoma de Barcelona
reponame_str	Dipòsit Digital de Documents de la UAB
collection	Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

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