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dc.contributor.authorWatson, MJ
dc.contributor.authorBerger, PL
dc.contributor.authorBanerjee, K
dc.contributor.authorFrank, SB
dc.contributor.authorTang, L
dc.contributor.authorGanguly, SS
dc.contributor.authorHostetter, G
dc.contributor.authorWinn, M
dc.contributor.authorMiranti, CK
dc.date.accessioned2021-05-04T01:28:49Z
dc.date.available2021-05-04T01:28:49Z
dc.date.issued2021-04-12
dc.identifier.citationWatson, M.J., Berger, P.L., Banerjee, K. et al. Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation. Oncogene (2021). https://doi.org/10.1038/s41388-021-01772-yen_US
dc.identifier.issn0950-9232
dc.identifier.urihttp://hdl.handle.net/10150/658113
dc.description.abstractThe molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.en_US
dc.description.sponsorshipDepartment of Defense, W81XWH-14-1-0479 and W81XWH-17-1-0570 NIH/NCI P30 CA023074en_US
dc.language.isoenen_US
dc.publisherNatureen_US
dc.rights© The Author(s), under exclusive licence to Springer Nature Limited 2021en_US
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en_US
dc.subjectprostate canceren_US
dc.subjectluminal differentiationen_US
dc.subjectPTENen_US
dc.subjectING4en_US
dc.subjectCREBen_US
dc.subjectJFKen_US
dc.titleAberrant CREB1 Activation in Prostate Cancer Disrupts Normal Prostate Luminal Cell Differentiationen_US
dc.typeArticleen_US
dc.contributor.departmentDepartment of Cellular and Molecular Medicine, University of Arizona Cancer Centeren_US
dc.identifier.journalOncogeneen_US
dc.description.note6 month embargo; published: 12 April 2021en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal accepted manuscripten_US


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