Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the lo...

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Authors: Avgustinova, Alexandra, Symeonidi, Aikaterini, Castellanos, Andrés, Urdiroz Urricelqui, Uxue, Solé Boldo, Llorenç, Martín, Mercè, Pérez Rodríguez, Ivan, Prats, Neus, Lehner, Ben, 1978-, Supek, Fran, Aznar Benitah, Salvador
Format: article
Status:Versión aceptada para publicación
Publication Date:2018
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/176381
Online Access:https://hdl.handle.net/2445/176381
Access Level:Open access
Keyword:Epigenètica
Metàstasi
Càncer de pell
Epigenetics
Metastasis
Skin cancer
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spelling Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumoursAvgustinova, AlexandraSymeonidi, AikateriniCastellanos, AndrésUrdiroz Urricelqui, UxueSolé Boldo, LlorençMartín, MercèPérez Rodríguez, IvanPrats, NeusLehner, Ben, 1978-Supek, FranAznar Benitah, SalvadorEpigenèticaMetàstasiCàncer de pellEpigeneticsMetastasisSkin cancerMutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.Nature Publishing Group2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/176381Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésversió postprint del document publicat a: https://doi.org/10.1038/s41556-018-0233-xNature Cell Biology, 2018, Vol. 20, num. 12, p. 1400-1409https://doi.org/10.1038/s41556-018-0233-xinfo:eu-repo/grantAgreement/EC/H2020/757700info:eu-repo/grantAgreement/EC/H2020/787041(c) Nature Publishing Group, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1763812026-05-27T06:46:51Z
dc.title.none.fl_str_mv Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
title Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
spellingShingle Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
Avgustinova, Alexandra
Epigenètica
Metàstasi
Càncer de pell
Epigenetics
Metastasis
Skin cancer
title_short Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
title_full Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
title_fullStr Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
title_full_unstemmed Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
title_sort Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours
dc.creator.none.fl_str_mv Avgustinova, Alexandra
Symeonidi, Aikaterini
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Solé Boldo, Llorenç
Martín, Mercè
Pérez Rodríguez, Ivan
Prats, Neus
Lehner, Ben, 1978-
Supek, Fran
Aznar Benitah, Salvador
author Avgustinova, Alexandra
author_facet Avgustinova, Alexandra
Symeonidi, Aikaterini
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Solé Boldo, Llorenç
Martín, Mercè
Pérez Rodríguez, Ivan
Prats, Neus
Lehner, Ben, 1978-
Supek, Fran
Aznar Benitah, Salvador
author_role author
author2 Symeonidi, Aikaterini
Castellanos, Andrés
Urdiroz Urricelqui, Uxue
Solé Boldo, Llorenç
Martín, Mercè
Pérez Rodríguez, Ivan
Prats, Neus
Lehner, Ben, 1978-
Supek, Fran
Aznar Benitah, Salvador
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Epigenètica
Metàstasi
Càncer de pell
Epigenetics
Metastasis
Skin cancer
topic Epigenètica
Metàstasi
Càncer de pell
Epigenetics
Metastasis
Skin cancer
description Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/176381
url https://hdl.handle.net/2445/176381
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv versió postprint del document publicat a: https://doi.org/10.1038/s41556-018-0233-x
Nature Cell Biology, 2018, Vol. 20, num. 12, p. 1400-1409
https://doi.org/10.1038/s41556-018-0233-x
info:eu-repo/grantAgreement/EC/H2020/757700
info:eu-repo/grantAgreement/EC/H2020/787041
dc.rights.none.fl_str_mv (c) Nature Publishing Group, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Nature Publishing Group, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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