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Zhao Z , Kurimchak A , Nikonova AS , Feiser F , Wasserman JS , Fowle H , Varughese T , Connors M , Johnson K , Makhov P , Lindskog C , Kolenko VM , Golemis EA , Duncan JS , Grana X
PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55alpha/PP2A reconstitution that triggers centrosome destabilization
Oncogenesis. 2019 Dec 10;8(12) :72
PMID: 31822657    PMCID: PMC6904742   
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Abstract
The PPP2R2A gene encodes the B55alpha 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 B55alpha 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 B55alpha reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55alpha-low cells also appear addicted to lower B55alpha expression, as even moderate increases in B55alpha expression are toxic. Reconstitution of B55alpha expression in prostate cancer (PCa) cell lines with low B55alpha expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55alpha reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55alpha/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 B55alpha. Thus, we propose the reduction in B55alpha levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55alpha reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55alpha activity.
Notes
Zhao, Ziran Kurimchak, Alison Nikonova, Anna S Feiser, Felicity Wasserman, Jason S Fowle, Holly Varughese, Tinsa Connors, Megan Johnson, Katherine Makhov, Petr Lindskog, Cecilia Kolenko, Vladimir M Golemis, Erica A ORCID: http://orcid.org/0000-0003-3618-3673 Duncan, James S Grana, Xavier ORCID: http://orcid.org/0000-0001-7134-0473 U54 CA221704/CA/NCI NIH HHS/United States R01 DK108195/DK/NIDDK NIH HHS/United States Journal Article United States Oncogenesis. 2019 Dec 10;8(12):72. doi: 10.1038/s41389-019-0180-9.