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DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway

2023-08Artigo científico Acesso aberto
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dc.contributor.authorVava, Akhona
dc.contributor.authorPaccez, Juliano D.
dc.contributor.authorPaccez, JD
dc.contributor.authorWang, Yihong
dc.contributor.authorGu, Xuesong
dc.contributor.authorBhasin, Manoj K.
dc.contributor.authorMyers, Michael
dc.contributor.authorSoares, Nelson C.
dc.contributor.authorLibermann, Towia A.
dc.contributor.authorLibermann, Towia
dc.contributor.authorZerbini, Luiz F.
dc.contributor.authorZerbini, Luiz
dc.contributor.institutionCentre for Toxicogenomics and Human Health (ToxOmics)
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.pblMDPI - Multidisciplinary Digital Publishing Institute
dc.date.accessioned2023-11-28T22:37:39Z
dc.date.available2023-11-28T22:37:39Z
dc.date.issued2023-08
dc.descriptionFunding Information: This research was funded by the International Centre for Genetic Engineering and Biotechnology (ICGEB). A.V. was funded by The South African National Research Foundation (NRF) Scarce Skills Doctoral scholarship and ICGEB fellowship; J.D.P. was funded by ICGEB Arturo Falaschi post-doctoral fellowship, and The South African National Research Foundation (NRF) Support for Rated and Unrated Researchers (Grant number SRUG2205067513); M.M. was funded by the ICGEB; N.C.S. was funded by University of Sharjah Targeted grant number 2301101775; T.A.L. was funded by NIH 1R21 CA187843–01; L.F.Z. was funded by the ICGEB. Publisher Copyright: © 2023 by the authors.
dc.description.abstractDefective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent3320908
dc.identifier.doi10.3390/cells12151973
dc.identifier.issn2073-4409
dc.identifier.otherPURE: 76715454
dc.identifier.otherPURE UUID: 59539f83-fac6-4d2a-873e-7454e6b920c3
dc.identifier.otherScopus: 85167591444
dc.identifier.otherPubMed: 37566052
dc.identifier.urihttp://hdl.handle.net/10362/160670
dc.identifier.urlhttps://www.scopus.com/pages/publications/85167591444
dc.language.isoeng
dc.peerreviewedyes
dc.subjectDCUN1D1
dc.subjectE3 ligase
dc.subjectneddylation
dc.subjectprostate cancer
dc.subjectWnt/β-catenin pathway
dc.subjectGeneral Biochemistry,Genetics and Molecular Biology
dc.subjectSDG 3 - Good Health and Well-being
dc.titleDCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathwayen
dc.typejournal article
degois.publication.issue15
degois.publication.titleCells
degois.publication.volume12
dspace.entity.typePublication
person.familyNamePaccez
person.familyNameLibermann
person.familyNameZerbini
person.givenNameJuliano
person.givenNameTowia
person.givenNameLuiz
person.identifier641565
person.identifier.orcid0000-0002-1086-4588
person.identifier.orcid0000-0002-4006-8179
person.identifier.orcid0000-0003-0736-9508
person.identifier.ridK-8560-2012
person.identifier.ridB-7720-2015
person.identifier.scopus-author-id12780814100
rcaap.rightsopenAccess
relation.isAuthorOfPublicationb1b1a93a-3635-40a3-baca-c28823b63f1c
relation.isAuthorOfPublication5e1a8ab5-ddc1-47fc-a084-a7f5cc8dc05e
relation.isAuthorOfPublication4a280cb2-308b-4447-b0d5-73f4e09a902f
relation.isAuthorOfPublication.latestForDiscovery5e1a8ab5-ddc1-47fc-a084-a7f5cc8dc05e

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