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dc.contributor.authorChen, J
dc.contributor.authorGuccini, I
dc.contributor.authorDi Mitri, D
dc.contributor.authorBrina, D
dc.contributor.authorRevandkar, A
dc.contributor.authorSarti, M
dc.contributor.authorPasquini, E
dc.contributor.authorAlajati, A
dc.contributor.authorPinton, S
dc.contributor.authorLosa, M
dc.contributor.authorCivenni, G
dc.contributor.authorCatapano, CV
dc.contributor.authorSgrignani, J
dc.contributor.authorCavalli, A
dc.contributor.authorD'Antuono, R
dc.contributor.authorAsara, JM
dc.contributor.authorMorandi, A
dc.contributor.authorChiarugi, P
dc.contributor.authorCrotti, S
dc.contributor.authorAgostini, M
dc.contributor.authorMontopoli, M
dc.contributor.authorMasgras, I
dc.contributor.authorRasola, A
dc.contributor.authorGarcia-Escudero, R
dc.contributor.authorDelaleu, N
dc.contributor.authorRinaldi, A
dc.contributor.authorBertoni, F
dc.contributor.authorBono, JD
dc.contributor.authorCarracedo, A
dc.contributor.authorAlimonti, A
dc.date.accessioned2020-11-11T12:15:50Z
dc.date.issued2018-02-01
dc.identifier.citationNature genetics, 2018, 50 (2), pp. 219 - 228
dc.identifier.issn1061-4036
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4223
dc.identifier.eissn1546-1718
dc.identifier.doi10.1038/s41588-017-0026-3
dc.description.abstractThe mechanisms by which mitochondrial metabolism supports cancer anabolism remain unclear. Here, we found that genetic and pharmacological inactivation of pyruvate dehydrogenase A1 (PDHA1), a subunit of the pyruvate dehydrogenase complex (PDC), inhibits prostate cancer development in mouse and human xenograft tumor models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both the mitochondria and the nucleus. Whereas nuclear PDC controls the expression of sterol regulatory element-binding transcription factor (SREBF)-target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated manner, thereby sustaining anabolism. Additionally, we found that PDHA1 and the PDC activator pyruvate dehydrogenase phosphatase 1 (PDP1) are frequently amplified and overexpressed at both the gene and protein levels in prostate tumors. Together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumorigenesis by controlling lipid biosynthesis, thus suggesting this complex as a potential target for cancer therapy.
dc.formatPrint-Electronic
dc.format.extent219 - 228
dc.languageeng
dc.language.isoeng
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCells, Cultured
dc.subjectCell Line, Tumor
dc.subjectCell Nucleus
dc.subjectCytoplasm
dc.subjectAnimals
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectProstatic Neoplasms
dc.subjectPyruvate Dehydrogenase Complex
dc.subjectPyruvate Dehydrogenase (Lipoamide)
dc.subjectCell Compartmentation
dc.subjectProtein Processing, Post-Translational
dc.subjectMale
dc.subjectLipogenesis
dc.titleCompartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer.
dc.typeJournal Article
dcterms.dateAccepted2017-12-01
rioxxterms.versionofrecord10.1038/s41588-017-0026-3
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-02
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature genetics
pubs.issue2
pubs.notesNot known
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublished
pubs.volume50
pubs.embargo.termsNot known
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorDe Bono, Johann


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