Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpressi...

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Autores: Albero, Robert, Enjuanes, Anna, Demajo, Santiago, Castellano, Giancarlo, Pinyol, Magda, García, Noelia, Capdevila, Cristina, Clot Razquin, Guillem, Suárez-Cisneros, Helena, Shimada, Mariko, Karube, Kennosuke, López-Guerra, Mónica, Colomer Pujol, Dolors, Beà Bobet, Sílvia M., Martín-Subero, José Ignacio, Campo Güerri, Elias, Jares Gerboles, Pedro
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/155233
Acceso en línea:https://hdl.handle.net/2445/155233
Access Level:acceso abierto
Palabra clave:Regulació cel·lular
Càncer
Limfomes
Cellular control mechanisms
Cancer
Lymphomas
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spelling Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasmsAlbero, RobertEnjuanes, AnnaDemajo, SantiagoCastellano, GiancarloPinyol, MagdaGarcía, NoeliaCapdevila, CristinaClot Razquin, GuillemSuárez-Cisneros, HelenaShimada, MarikoKarube, KennosukeLópez-Guerra, MónicaColomer Pujol, DolorsBeà Bobet, Sílvia M.Martín-Subero, José IgnacioCampo Güerri, EliasJares Gerboles, PedroRegulació cel·lularCàncerLimfomesCellular control mechanismsCancerLymphomasCyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.American Society for Clinical Investigation2020202020182020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion17 p.application/pdfhttps://hdl.handle.net/2445/155233Articles publicats en revistes (Fonaments Clínics)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1172/JCI96520Journal of Clinical Investigation, 2018, vol. 128, num. 9, p. 4132-4147https://doi.org/10.1172/JCI96520(c) American Society for Clinical Investigation, 2018info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1552332026-05-29T05:05:01Z
dc.title.none.fl_str_mv Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
title Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
spellingShingle Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
Albero, Robert
Regulació cel·lular
Càncer
Limfomes
Cellular control mechanisms
Cancer
Lymphomas
title_short Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
title_full Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
title_fullStr Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
title_full_unstemmed Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
title_sort Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms
dc.creator.none.fl_str_mv Albero, Robert
Enjuanes, Anna
Demajo, Santiago
Castellano, Giancarlo
Pinyol, Magda
García, Noelia
Capdevila, Cristina
Clot Razquin, Guillem
Suárez-Cisneros, Helena
Shimada, Mariko
Karube, Kennosuke
López-Guerra, Mónica
Colomer Pujol, Dolors
Beà Bobet, Sílvia M.
Martín-Subero, José Ignacio
Campo Güerri, Elias
Jares Gerboles, Pedro
author Albero, Robert
author_facet Albero, Robert
Enjuanes, Anna
Demajo, Santiago
Castellano, Giancarlo
Pinyol, Magda
García, Noelia
Capdevila, Cristina
Clot Razquin, Guillem
Suárez-Cisneros, Helena
Shimada, Mariko
Karube, Kennosuke
López-Guerra, Mónica
Colomer Pujol, Dolors
Beà Bobet, Sílvia M.
Martín-Subero, José Ignacio
Campo Güerri, Elias
Jares Gerboles, Pedro
author_role author
author2 Enjuanes, Anna
Demajo, Santiago
Castellano, Giancarlo
Pinyol, Magda
García, Noelia
Capdevila, Cristina
Clot Razquin, Guillem
Suárez-Cisneros, Helena
Shimada, Mariko
Karube, Kennosuke
López-Guerra, Mónica
Colomer Pujol, Dolors
Beà Bobet, Sílvia M.
Martín-Subero, José Ignacio
Campo Güerri, Elias
Jares Gerboles, Pedro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Regulació cel·lular
Càncer
Limfomes
Cellular control mechanisms
Cancer
Lymphomas
topic Regulació cel·lular
Càncer
Limfomes
Cellular control mechanisms
Cancer
Lymphomas
description Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.
publishDate 2018
dc.date.none.fl_str_mv 2018
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/155233
url https://hdl.handle.net/2445/155233
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1172/JCI96520
Journal of Clinical Investigation, 2018, vol. 128, num. 9, p. 4132-4147
https://doi.org/10.1172/JCI96520
dc.rights.none.fl_str_mv (c) American Society for Clinical Investigation, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Society for Clinical Investigation, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 17 p.
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv Articles publicats en revistes (Fonaments Clínics)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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