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dc.creatorZhao, Ziran
dc.creatorKurimchak, Alison
dc.creatorNikonova, Anna S.
dc.creatorFeiser, Felicity
dc.creatorWasserman, Jason
dc.creatorFowle, Holly
dc.creatorVarughese, Tinsa
dc.creatorConnors, Megan
dc.creatorJohnson, Katherine
dc.creatorMakhov, Petr
dc.creatorLindskog, Cecilia
dc.creatorKolenko, Vladimir M.
dc.creatorGolemis, Erica
dc.creatorDuncan, James
dc.creatorGrana, Xavier
dc.identifier.citationZhao Z, Kurimchak A, Nikonova AS, Feiser F, Wasserman JS, Fowle H, et al. PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization. Oncogenesis. 2019 Dec 10;8:72. doi:10.1038/s41389-019-0180-9.
dc.description.abstractThe PPP2R2A gene encodes the B55α regulatory subunit of PP2A. Here, we report that PPP2R2A is hemizygously lost in ~42% of prostate adenocarcinomas, correlating with reduced expression, poorer prognosis, and an increased incidence of hemizygous loss (>75%) in metastatic disease. Of note, PPP2R2A homozygous loss is less common (5%) and not increased at later tumor stages. Reduced expression of B55α is also seen in prostate tumor tissue and cell lines. Consistent with the possibility that complete loss of PPP2R2A is detrimental in prostate tumors, PPP2R2A deletion in cells with reduced but present B55α reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55α-low cells also appear addicted to lower B55α expression, as even moderate increases in B55α expression are toxic. Reconstitution of B55α expression in prostate cancer (PCa) cell lines with low B55α expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55α reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55α/PP2A and the vertebrate centrosome. These effects are dependent on a prolonged metaphase/anaphase checkpoint and are lethal to PCa cells addicted to low levels of B55α. Thus, we propose the reduction in B55α levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55α reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55α activity.
dc.format.extent16 pages
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartOncogenesis, Vol. 8
dc.rightsAttribution CC BY
dc.subjectProstate cancer
dc.titlePPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization
dc.type.genreJournal article
dc.contributor.groupFels Institute for Cancer Research and Molecular Biology (Temple University)
dc.contributor.groupFox Chase Cancer Center (Temple University)
dc.description.departmentCancer and Cellular Biology
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.description.schoolcollegeLewis Katz School of Medicine
dc.temple.creatorZhao, Ziran
dc.temple.creatorKurimchak, Alison
dc.temple.creatorNikonova, Anna S.
dc.temple.creatorFeiser, Felicity
dc.temple.creatorWasserman, Jason S.
dc.temple.creatorFowle, Holly
dc.temple.creatorVarughese, Tinsa
dc.temple.creatorConnors, Megan
dc.temple.creatorJohnson, Katherine
dc.temple.creatorMakhov, Petr
dc.temple.creatorKolenko, Vladimir M.
dc.temple.creatorGolemis, Erica A.
dc.temple.creatorDuncan, James S.
dc.temple.creatorGraña, Xavier

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