ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer

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dc.contributor.authorQian, Chen
dc.contributor.authorYang, Qian
dc.contributor.authorRotinen Díaz, Mirja Sofia
dc.contributor.authorHuang, Rongrong
dc.contributor.authorKim, Hyoyoung
dc.contributor.authorGallent, Brad
dc.contributor.authorYan, Yiwu
dc.contributor.authorCadaneanu, Radu M.
dc.contributor.authorZhang, Baohui
dc.contributor.authorKaochar, Salma
dc.contributor.authorFreedland, Stephen J.
dc.contributor.authorPosadas, Edwin M.
dc.contributor.authorEllis, Leigh
dc.contributor.authorDi Vizio, Dolores
dc.contributor.authorMorrissey, Colm
dc.contributor.authorNelson, Peter S.
dc.contributor.authorBrady, Lauren
dc.contributor.authorMurali, Ramachandran
dc.contributor.authorCampbell, Moray J.
dc.contributor.authorYang, Wei
dc.contributor.authorKnudsen, Beatrice S.
dc.contributor.authorMostaghel, Elahe A.
dc.contributor.authorYe, Huihui
dc.contributor.authorGarraway, Isla P.
dc.contributor.authorYou, Sungyong
dc.contributor.authorFreeman, Michael R.
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.departmentInstitute for Multidisciplinary Research in Applied Biology - IMABen
dc.date.accessioned2024-11-06T09:54:32Z
dc.date.available2024-11-06T09:54:32Z
dc.date.issued2024-06-27
dc.date.updated2024-11-06T09:49:50Z
dc.description.abstractAndrogen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.en
dc.description.sponsorshipUCLA Prostate Cancer SPORE [2P50CA092131, 1R01CA220327, 1R01CA271750]; Department of Defense [PC180541, PC190604, PC190482]; Institute for Prostate Cancer Research, the Pacific Northwest Prostate Cancer SPORE [P50CA97186, R01CA266452, R01 CA234715, R21 CA277368]. Funding for open access charge: NIH.
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dc.format.mimetypeapplication/zipen
dc.identifier.citationQian, C., Yang, Q., Rotinen, M., Huang, R., Kim, H., Gallent, B., Yan, Y., Cadaneanu, R. M., Zhang, B., Kaochar, S., Freedland, S. J., Posadas, E. M., Ellis, L., Vizio, D. D., Morrissey, C., Nelson, P. S., Brady, L., Murali, R., Campbell, M. J., Yang, W., Knudsen, B. S., Mostaghel, E. A., Ye, H., Garraway, I. P., You, S., Freeman, M. R. (2024). ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer. Nucleic Acids Research, 52(13), 7740-7760. https://doi.org/10.1093/nar/gkae547.
dc.identifier.doi10.1093/nar/gkae547
dc.identifier.issn0305-1048
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52455
dc.language.isoeng
dc.publisherOxford University Press
dc.relation.ispartofNucleic Acids Research (2024), vol. 52, núm. 13
dc.relation.publisherversionhttps://doi.org/10.1093/nar/gkae547
dc.rights© The Author(s) 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectONECUT2en
dc.subjectAdenocarcinomaen
dc.subjectHormonal therapyen
dc.titleONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate canceren
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationecbb6fbe-3bda-4cad-945f-f263c1af5981
relation.isAuthorOfPublication.latestForDiscoveryecbb6fbe-3bda-4cad-945f-f263c1af5981

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