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

• The PPP2R2A gene encodes the B55 alpha regulatory subunit of PP2A. Here, we report that PPP2R2A is hemizygously lost in similar to 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 alpha 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 alpha reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55 alpha-low cells also appear addicted to lower B55 alpha expression, as even moderate increases in B55 alpha expression are toxic. Reconstitution of B55 alpha expression in prostate cancer (PCa) cell lines with low B55 alpha expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55 alpha reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55 alpha/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 alpha. Thus, we propose the reduction in B55 alpha levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55 alpha 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 alpha activity.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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