Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks

Autores
Bayo Fina, Juan Miguel; Tran, Tram Anh; Wang, Lei; Peña Llopis, Samuel; Das, Amit K.; Martinez, Elisabeth D.
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
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
Fil: Tran, Tram Anh. University of Texas Medical Branch; Estados Unidos
Fil: Wang, Lei. University of Texas Medical Branch; Estados Unidos
Fil: Peña Llopis, Samuel. Essen University Hospital; Alemania
Fil: Das, Amit K.. University of Texas Medical Branch; Estados Unidos
Fil: Martinez, Elisabeth D.. University of Texas Medical Branch; Estados Unidos
Materia
DNA REPAIR
H3K4ME3
JARID
JIB-04
JUMONJI KDM
KDM5B
LUNG CANCER
RADIATION THERAPY
RADIORESISTANCE
RADIOSENSITIZATION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/88754
Acceder
id CONICETDig_752a41ef333d92d3e364c5ed0a88218e
oai_identifier_str oai:ri.conicet.gov.ar:11336/88754
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand BreaksBayo Fina, Juan MiguelTran, Tram AnhWang, LeiPeña Llopis, SamuelDas, Amit K.Martinez, Elisabeth D.DNA REPAIRH3K4ME3JARIDJIB-04JUMONJI KDMKDM5BLUNG CANCERRADIATION THERAPYRADIORESISTANCERADIOSENSITIZATIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3We 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.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; ArgentinaFil: Tran, Tram Anh. University of Texas Medical Branch; Estados UnidosFil: Wang, Lei. University of Texas Medical Branch; Estados UnidosFil: Peña Llopis, Samuel. Essen University Hospital; AlemaniaFil: Das, Amit K.. University of Texas Medical Branch; Estados UnidosFil: Martinez, Elisabeth D.. University of Texas Medical Branch; Estados UnidosElsevier2018-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88754Bayo 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.e52211-1247CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2018.09.081info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2211124718315419info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-26T09:06:23Zoai:ri.conicet.gov.ar:11336/88754instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-26 09:06:24.16CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
title Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
spellingShingle Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
Bayo Fina, Juan Miguel
DNA REPAIR
H3K4ME3
JARID
JIB-04
JUMONJI KDM
KDM5B
LUNG CANCER
RADIATION THERAPY
RADIORESISTANCE
RADIOSENSITIZATION
title_short Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
title_full Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
title_fullStr Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
title_full_unstemmed Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
title_sort Jumonji Inhibitors Overcome Radioresistance in Cancer through Changes in H3K4 Methylation at Double-Strand Breaks
dc.creator.none.fl_str_mv Bayo Fina, Juan Miguel
Tran, Tram Anh
Wang, Lei
Peña Llopis, Samuel
Das, Amit K.
Martinez, Elisabeth D.
author Bayo Fina, Juan Miguel
author_facet Bayo Fina, Juan Miguel
Tran, Tram Anh
Wang, Lei
Peña Llopis, Samuel
Das, Amit K.
Martinez, Elisabeth D.
author_role author
author2 Tran, Tram Anh
Wang, Lei
Peña Llopis, Samuel
Das, Amit K.
Martinez, Elisabeth D.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv DNA REPAIR
H3K4ME3
JARID
JIB-04
JUMONJI KDM
KDM5B
LUNG CANCER
RADIATION THERAPY
RADIORESISTANCE
RADIOSENSITIZATION
topic DNA REPAIR
H3K4ME3
JARID
JIB-04
JUMONJI KDM
KDM5B
LUNG CANCER
RADIATION THERAPY
RADIORESISTANCE
RADIOSENSITIZATION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
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
Fil: Tran, Tram Anh. University of Texas Medical Branch; Estados Unidos
Fil: Wang, Lei. University of Texas Medical Branch; Estados Unidos
Fil: Peña Llopis, Samuel. Essen University Hospital; Alemania
Fil: Das, Amit K.. University of Texas Medical Branch; Estados Unidos
Fil: Martinez, Elisabeth D.. University of Texas Medical Branch; Estados Unidos
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/88754
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
2211-1247
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88754
identifier_str_mv 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
2211-1247
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2018.09.081
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2211124718315419
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1849873464534499328
score 13.011256

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