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 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.

中文翻译：

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PPP2R2A前列腺癌单倍体功能不全与预后较差和对B55α/ PP2A重构的高度脆弱性有关，后者会触发中心体失稳。

PPP2R2A基因编码PP2A的B55α调节亚基。在这里，我们报道PPP2R2A在约42％的前列腺腺癌中是半合子丢失的，与表达降低，预后较差和转移性疾病中半合子丢失的发生率增加（> 75％）相关。值得注意的是，PPP2R2A纯合性丢失较少见（5％），并且在肿瘤的晚期不增加。在前列腺肿瘤组织和细胞系中也观察到B55α表达降低。与PPP2R2A完全丧失对前列腺肿瘤有害的可能性相一致，B55α减少但存在的B55α细胞中PPP2R2A缺失会通过减缓整个细胞周期的进程来降低细胞增殖。值得注意的是，低水平的B55α细胞也似乎沉迷于较低的B55α表达，因为即使适度增加B55α的表达也是有毒的。在低B55α表达的前列腺癌（PCa）细胞系中重建B55α表达可降低增殖，抑制转化并阻止异种移植的致瘤性。从机制上讲，我们显示B55α的重组减少了中心体维持必需蛋白质的磷酸化，并诱导中心体崩溃和染色体分离失败。首次报道了B55α/ PP2A与脊椎动物中心体之间的联系。这些作用取决于延长的中期/后期检查点，对沉迷于低水平B55α的PCa细胞具有致命性。因此，我们提出与半合子丢失相关的B55α水平的降低对于PCa细胞中心体完整性是必要的，从而导致B55α重构的选择性致死性。