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JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.

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dc.contributor.authorPaschalis, Alec
dc.contributor.authorWelti, Jonathan
dc.contributor.authorNeeb, Antje J
dc.contributor.authorYuan, Wei
dc.contributor.authorFigueiredo, Ines
dc.contributor.authorPereira, Rita
dc.contributor.authorFerreira, Ana
dc.contributor.authorRiisnaes, Ruth
dc.contributor.authorRodrigues, Daniel Nava
dc.contributor.authorJimenez-Vacas, Juan M
dc.contributor.authorKim, Soojin
dc.contributor.authorUo, Takuma
dc.contributor.authorMicco, Patrizio Di
dc.contributor.authorTumber, Anthony
dc.contributor.authorIslam, Md Saiful
dc.contributor.authorMoesser, Marc A
dc.contributor.authorAbboud, Martine
dc.contributor.authorKawamura, Akane
dc.contributor.authorGurel, Bora
dc.contributor.authorChristova, Rossitza
dc.contributor.authorGil, Veronica S
dc.contributor.authorBuroni, Lorenzo
dc.contributor.authorCrespo, Mateus
dc.contributor.authorMiranda, Susana
dc.contributor.authorLambros, Maryou B
dc.contributor.authorCarreira, Suzanne
dc.contributor.authorTunariu, Nina
dc.contributor.authorAlimonti, Andrea
dc.contributor.authorAl-Lazikani, Bissan
dc.contributor.authorSchofield, Christopher J
dc.contributor.authorPlymate, Stephen R
dc.contributor.authorSharp, Adam
dc.contributor.authorde Bono, Johann S
dc.contributor.funderEuropean Research Council
dc.contributor.funderProstate Cancer UK Research Innovation Award
dc.contributor.funderCRUK
dc.contributor.groupSU2C/PCF International Prostate Cancer Dream Team
dc.date.accessioned2023-02-09T10:50:35Z
dc.date.available2023-02-09T10:50:35Z
dc.date.issued2020-12-02
dc.description.abstractEndocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P< 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P ¼ 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease.
dc.description.sponsorshipResearch supported by an Stand Up To CancerProstate Cancer Dream Team Translational Research Grant (SU2C-AACRDT0712). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. This research was funded by Cancer Research UK and a Prostate Cancer UK Research Innovation Award (RIA17-ST2-014). A. Alimonti was supported by European Research Council Consolidator Grant (683136); Swiss Cancer League (4267); Swiss National Science Foundation (176045); Prostate Cancer Foundation (19CHAL08); and Italian Association for Cancer Research Investigator Grant (22030). C.J. Schofield and A. Kawamura thank CRUK (C8717/A18245) and the Wellcome Trust (106244/Z/14/Z) for funding. S.R. Plymate gratefully acknowledges DOD Grants W81XWH-17-0323 and W81XWH-20-0146 (S.R. Plymate) and DOD W81XWH-17-0414 (S.R. Plymate) and Veterans Affairs Research Service Merit Award and Senior Clinician Scientist Research Award. A. Sharp also gratefully acknowledges previous research funding from the Academy of Medical Sciences, the Medical Research Council, and Prostate Cancer UK, and current funding from the Prostate Cancer Foundation and Wellcome Trust. J.S. de Bono also gratefully acknowledges research funding from Prostate Cancer UK and the Movember Foundation through the London Movember Centre of Excellence (CEO13_2-002), the Prostate Cancer Foundation, Stand Up To Cancer, the UK Department of Health through an Experimental Cancer Medicine Centre grant, and the US Department of Defense. Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
dc.description.versionSi
dc.identifier.citationPaschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, et al. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Cancer Res. 2021 Feb 15;81(4):1087-1100
dc.identifier.doi10.1158/0008-5472.CAN-20-1807
dc.identifier.essn1538-7445
dc.identifier.pmcPMC8025710
dc.identifier.pmid33822745
dc.identifier.pubmedURLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025710/pdf
dc.identifier.unpaywallURLhttps://aacrjournals.org/cancerres/article-pdf/81/4/1087/3165369/1087.pdf
dc.identifier.urihttp://hdl.handle.net/10668/17533
dc.issue.number4
dc.journal.titleCancer research
dc.journal.titleabbreviationCancer Res
dc.language.isoen
dc.organizationHospital Universitario Reina Sofía
dc.organizationInstituto Maimónides de Investigación Biomédica de Córdoba-IMIBIC
dc.page.number1087-1100
dc.provenanceRealizada la curación de contenido 19/08/2024
dc.publisherAmerican Association for Cancer Research
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, N.I.H., Extramural
dc.pubmedtypeResearch Support, Non-U.S. Gov't
dc.pubmedtypeResearch Support, U.S. Gov't, Non-P.H.S.
dc.relation.projectID683136
dc.relation.projectIDIA17-ST2-014
dc.relation.projectIDC8717/A18245
dc.relation.publisherversionhttps://aacrjournals.org/cancerres/article-lookup/doi/10.1158/0008-5472.CAN-20-1807
dc.rights.accessRightsopen access
dc.subjectAlternative splicing
dc.subjectAntineoplastic agents
dc.subjectCell line, tumor
dc.subjectCohort studies
dc.subjectEnzyme inhibitors
dc.subjectGene expression regulation, neoplastic
dc.subject.decsHistona demetilasas con dominio de Jumonji
dc.subject.decsIsoformas de proteínas
dc.subject.decsNeoplasias de la próstata resistentes a la castración
dc.subject.decsOxigenasas
dc.subject.decsPronóstico
dc.subject.decsReceptores androgénicos
dc.subject.decsTerapia molecular dirigida
dc.subject.meshHumans
dc.subject.meshJumonji domain-containing histone demethylases
dc.subject.meshMale
dc.subject.meshMolecular targeted therapy
dc.subject.meshOxygenases
dc.subject.meshPrognosis
dc.subject.meshProstatic neoplasms, castration-resistant
dc.subject.meshProtein isoforms
dc.subject.meshReceptors, androgen
dc.subject.meshRetrospective studies
dc.titleJMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
dc.typeresearch article
dc.type.hasVersionVoR
dc.volume.number81
dspace.entity.typePublication

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