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dc.contributor.author
Bayo Fina, Juan Miguel
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Tran, Tram Anh
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Wang, Lei
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Peña Llopis, Samuel
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Das, Amit K.
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Martinez, Elisabeth D.
dc.date.available
2019-11-13T18:29:55Z
dc.date.issued
2018-10
dc.identifier.citation
Bayo Fina, Juan Miguel; Tran, Tram Anh; Wang, Lei; Peña Llopis, Samuel; Das, Amit K.; et al.; Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks; Elsevier; Cell Reports; 25; 4; 10-2018; 1040-1050.e5
dc.identifier.issn
2211-1247
dc.identifier.uri
http://hdl.handle.net/11336/88754
dc.description.abstract
We have uncovered a role for Jumonji inhibitors in overcoming radioresistance through KDM5B inhibition. Pharmacological blockade of Jumonji demethylases with JIB-04 leads to specific accumulation of H3K4me3 at sites marked by γH2AX and impaired recruitment of DNA repair factors, preventing resolution of damage and resulting in robust sensitization to radiation therapy. In DNA-repair-proficient cancer cells, knockdown of the H3K4me3 demethylase KDM5B, but not other Jumonji enzymes, mimics pharmacological inhibition, and KDM5B overexpression rescues this phenotype and increases radioresistance. The H3K4me3 demethylase inhibitor PBIT also sensitizes cancer cells to radiation, while an H3K27me3 demethylase inhibitor does not. In vivo co-administration of radiation with JIB-04 significantly prolongs the survival of mice with tumors even long after cessation of treatment. In human patients, lung squamous cell carcinomas highly expressing KDM5B respond poorly to radiation. Thus, we propose the use of Jumonji KDM inhibitors as potent radiosensitizers. Radioresistance is an obstacle to lung cancer cures. Bayo et al. reveal that JARID1B removes H3K4me3 marks at sites of DNA damage. Genetic or pharmacological inhibition of JARID1B robustly radiosensitizes cancers in vitro and in vivo through defects in DNA repair, providing a therapeutic option for radioresistant tumors.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
DNA REPAIR
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H3K4ME3
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JARID
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JIB-04
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JUMONJI KDM
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KDM5B
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LUNG CANCER
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RADIATION THERAPY
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RADIORESISTANCE
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RADIOSENSITIZATION
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Otras Medicina Básica
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-10-17T14:58:54Z
dc.journal.volume
25
dc.journal.number
4
dc.journal.pagination
1040-1050.e5
dc.journal.pais
Estados Unidos
dc.description.fil
Fil: Bayo Fina, Juan Miguel. Universidad Austral; Argentina. University of Texas Medical Branch; Estados Unidos. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
dc.description.fil
Fil: Tran, Tram Anh. University of Texas Medical Branch; Estados Unidos
dc.description.fil
Fil: Wang, Lei. University of Texas Medical Branch; Estados Unidos
dc.description.fil
Fil: Peña Llopis, Samuel. Essen University Hospital; Alemania
dc.description.fil
Fil: Das, Amit K.. University of Texas Medical Branch; Estados Unidos
dc.description.fil
Fil: Martinez, Elisabeth D.. University of Texas Medical Branch; Estados Unidos
dc.journal.title
Cell Reports
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.celrep.2018.09.081
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2211124718315419
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