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dc.contributor.authorWalters, ZS
dc.contributor.authorAladowicz, E
dc.contributor.authorVillarejo-Balcells, B
dc.contributor.authorNugent, G
dc.contributor.authorSelfe, JL
dc.contributor.authorEve, P
dc.contributor.authorBlagg, J
dc.contributor.authorRossanese, O
dc.contributor.authorShipley, J
dc.date.accessioned2021-06-03T09:09:10Z
dc.date.available2021-06-03T09:09:10Z
dc.date.issued2021-04-06
dc.identifier.citationCancers, 2021, 13 (7)
dc.identifier.issn2072-6694
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4595
dc.identifier.eissn2072-6694
dc.identifier.doi10.3390/cancers13071734
dc.description.abstractHistone demethylases are epigenetic modulators that play key roles in regulating gene expression related to many critical cellular functions and are emerging as promising therapeutic targets in a number of tumor types. We previously identified histone demethylase family members as overexpressed in the pediatric sarcoma, rhabdomyosarcoma. Here we show high sensitivity of rhabdomyosarcoma cells to a pan-histone demethylase inhibitor, JIB-04 and identify a key role for the histone demethylase KDM4B in rhabdomyosarcoma cell growth through an RNAi-screening approach. Decreasing KDM4B levels affected cell cycle progression and transcription of G1/S and G2/M checkpoint genes including CDK6 and CCNA2 , which are bound by KDM4B in their promoter regions. However, after sustained knockdown of KDM4B, rhabdomyosarcoma cell growth recovered. We show that this can be attributed to acquired molecular compensation via recruitment of KDM4A to the promoter regions of CDK6 and CCNA2 that are otherwise bound by KDM4B. Furthermore, upfront silencing of both KDM4B and KDM4A led to RMS cell apoptosis, not seen by reducing either alone. To circumvent compensation and elicit stronger therapeutic responses, our study supports targeting histone demethylase sub-family proteins through selective poly-pharmacology as a therapeutic approach.
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleRole for the Histone Demethylase KDM4B in Rhabdomyosarcoma via CDK6 and CCNA2: Compensation by KDM4A and Apoptotic Response of Targeting Both KDM4B and KDM4A.
dc.typeJournal Article
dcterms.dateAccepted2021-04-04
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3390/cancers13071734
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-04-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancers
pubs.issue7
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology
pubs.publication-statusPublished
pubs.volume13
pubs.embargo.termsNo embargo
icr.researchteamTarget Evaluation and Molecular Therapeutics
icr.researchteamSarcoma Molecular Pathology
icr.researchteamTarget Evaluation and Molecular Therapeuticsen_US
icr.researchteamSarcoma Molecular Pathologyen_US
dc.contributor.icrauthorShipley, Janeten
dc.contributor.icrauthorRossanese, Oliviaen
dc.contributor.icrauthorJohnson, Sarahen


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