Loss of dnmt3a and dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-g
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- dc.contributor.author Rinaldi, Lorenzo, 1986-ca
- dc.contributor.author Avgustinova, Alexandraca
- dc.contributor.author Martín, Mercèca
- dc.contributor.author Datta, Debayanca
- dc.contributor.author Solanas, Guiomarca
- dc.contributor.author Prats, Neusca
- dc.contributor.author Aznar Benitah, Salvadorca
- dc.date.accessioned 2018-05-29T10:25:01Z
- dc.date.available 2018-05-29T10:25:01Z
- dc.date.issued 2017
- dc.description.abstract The DNA methyltransferase Dnmt3a suppresses tumorigenesis in models of leukemia and lung cancer. Conversely, deregulation of Dnmt3b is thought to generally promote tumorigenesis. However, the role of Dnmt3a and Dnmt3b in many types of cancer remains undefined. Here, we show that Dnmt3a and Dnmt3b are dispensable for homeostasis of the murine epidermis. However, loss of Dnmt3a-but not Dnmt3b-increases the number of carcinogen-induced squamous tumors, without affecting tumor progression. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous carcinomas become more aggressive and metastatic. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers and inhibits the expression of lipid metabolism genes, including PPAR-γ, by directly methylating their promoters. Importantly, inhibition of PPAR-γ partially prevents the increase in tumorigenesis upon deletion of Dnmt3a. Altogether, we demonstrate that Dnmt3a and Dnmt3b protect the epidermis from tumorigenesis and that squamous carcinomas are sensitive to inhibition of PPAR-γ.
- dc.description.sponsorship The Spanish Ministry of Economy and Development (MINECO), and the Institute supported this project in the laboratory of SAB for Research in Biomedicine (IRB-Barcelona). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We are very grateful to the laboratories of Rudolph Jaenisch and Rafii Ahmed for providing us the Dnmt3a and Dnmt3b flox/flox animals. LR was sponsored by La Caixa International PhD fellowship. We thank all the core facilities at the IRB-Barcelona for their assistance in our work, and Veronica Raker for editing the manuscript. The raw data for every dataset included in the manuscript can be found at GEO (GSE87412).
- dc.format.mimetype application/pdf
- dc.identifier.citation Rinaldi L, Avgustinova A, Martín M, Datta D, Solanas G, Prats N et al. Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gamma. Elife. 2017 Apr 20;6:e21697. DOI: 10.7554/eLife.21697
- dc.identifier.doi http://dx.doi.org/10.7554/eLife.21697
- dc.identifier.issn 2050-084X
- dc.identifier.uri http://hdl.handle.net/10230/34746
- dc.language.iso eng
- dc.publisher eLifeca
- dc.relation.ispartof Elife. 2017 Apr 20;6:e21697
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309502
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-47990-P
- dc.rights © 2017, Rinaldi et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Dna methylation
- dc.subject.keyword Pparg
- dc.subject.keyword Cancer biology
- dc.subject.keyword Developmental biology
- dc.subject.keyword Enhancers
- dc.subject.keyword Promoters
- dc.subject.keyword Squamous cell carcinomas
- dc.subject.keyword Stem cells
- dc.subject.keyword Transcriptional regulation
- dc.title Loss of dnmt3a and dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion