Dataset Information

PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55?/PP2A reconstitution that triggers centrosome destabilization.

ABSTRACT: The PPP2R2A gene encodes the B55? 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 B55? 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 B55? reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55?-low cells also appear addicted to lower B55? expression, as even moderate increases in B55? expression are toxic. Reconstitution of B55? expression in prostate cancer (PCa) cell lines with low B55? expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55? reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55?/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 B55?. Thus, we propose the reduction in B55? levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55? reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55? activity.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC6904742 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization.

Zhao Ziran Z Kurimchak Alison A Nikonova Anna S AS Feiser Felicity F Wasserman Jason S JS Fowle Holly H Varughese Tinsa T Connors Megan M Johnson Katherine K Makhov Petr P Lindskog Cecilia C Kolenko Vladimir M VM Golemis Erica A EA Duncan James S JS Graña Xavier X

Oncogenesis 20191210 12

The 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 ...[more]

PMID: 31822657

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Project description:The serine/threonine protein phosphatase 2A (PP2A) is a master regulator of the complex cellular signaling that occurs during all stages of mammalian development. PP2A is composed of a catalytic, a structural, and regulatory subunit, for which there are multiple isoforms. The association of specific regulatory subunits determines substrate specificity and localization of phosphatase activity, however, the precise role of each regulatory subunit in development is not known. Here we report the generation of the first knockout mouse for the Ppp2r2a gene, encoding the PP2A-B55? regulatory subunit, using CRISPR/Cas9. Heterozygous animals developed and grew as normal, however, homozygous knockout mice were not viable. Analysis of embryos at different developmental stages found a normal Mendelian ratio of Ppp2r2a-/- embryos at embryonic day (E) 10.5 (25%), but reduced Ppp2r2a-/- embryos at E14.5 (18%), and further reduced at E18.5 (10%). No live Ppp2r2a-/- pups were observed at birth. Ppp2r2a-/- embryos were significantly smaller than wild-type or heterozygous littermates and displayed a variety of neural defects such as exencephaly, spina bifida, and cranial vault collapse, as well as syndactyly and severe epidermal defects; all processes driven by growth and differentiation of the ectoderm. Ppp2r2a-/- embryos had incomplete epidermal barrier acquisition, associated with thin, poorly differentiated stratified epithelium with weak attachment to the underlying dermis. The basal keratinocytes in Ppp2r2a-/- embryos were highly disorganized, with reduced immunolabeling of integrins and basement membrane proteins, suggesting impaired focal adhesion and hemidesmosome assembly. The spinous and granular layers were thinner in the Ppp2r2a-/- embryos, with aberrant expression of adherens and tight junction associated proteins. The overlying stratum corneum was either absent or incomplete. Thus PP2A-B55? is an essential regulator of epidermal stratification, and is essential for ectodermal development during embryogenesis.

Dataset Information

PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55?/PP2A reconstitution that triggers centrosome destabilization.

Publications

PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization.

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