PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55α/PP2A reconstitution that triggers centrosome destabilization.
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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PPP2R2A 前列腺癌单倍体不足与较差的预后和极易引发中心体不稳定的 B55α/PP2A 重建有关。
DOI：
10.1038/s41389-019-0180-9
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发表时间：
2019
期刊：
影响因子：
6.2
通讯作者：
Graña,Xav
中科院分区：
文献类型：
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作者：
Zhao,Ziran;Kurimchak,Alison;Nikonova,AnnaS;Feiser,Felicity;Wasserman,JasonS;Fowle,Holly;Varughese,Tinsa;Connors,Megan;Johnson,Katherine;Makhov,Petr;Lindskog,Cecilia;Kolenko,VladimirM;Golemis,EricaA;Duncan,JamesS;Graña,Xav
PPP 2 R2 A基因编码PP 2A的B55α调节亚基。在此，我们报道PPP 2 R2 A在~42%的前列腺癌中半合子丢失，与表达减少、预后差和转移性疾病中半合子丢失发生率增加（>75%）相关。值得注意的是，PPP 2 R2 A纯合丢失不太常见（5%），并且在肿瘤后期不会增加。在前列腺肿瘤组织和细胞系中也观察到B55α表达减少。与PPP 2 R2 A的完全缺失在前列腺肿瘤中有害的可能性一致，在B55α减少但存在的细胞中PPP 2 R2 A缺失通过减缓细胞周期的进展来降低细胞增殖。值得注意的是，B55α-低细胞似乎也对较低的B55α表达上瘾，因为即使B55α表达的中度增加也是有毒的。在具有低B55α表达的前列腺癌（PCa）细胞系中重建B55 α表达降低增殖、抑制转化并阻断异种移植物致瘤性。从机制上讲，我们发现B55α重建减少了中心体维持所必需的蛋白质的磷酸化，并诱导中心体崩溃和染色体分离失败;这是B55α/PP 2A与脊椎动物中心体之间的首次报道。这些作用依赖于延长的中期/后期检查点，并且对依赖于低水平B55α的PCa细胞是致命的。因此，我们提出，与半合子丢失相关的B55α水平的降低是PCa细胞中心体完整性所必需的，导致B55α重建的选择性致死性。这种脆弱性可以通过增强PP 2A/B55α活性的药理学方法，在大量的PPP 2 R2 A半合子缺失患者中进行治疗。
ThePPP2R2Agene encodes the B55α regulatory subunit of PP2A. Here, we report thatPPP2R2Ais 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,PPP2R2Ahomozygous 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 ofPPP2R2Ais detrimental in prostate tumors,PPP2R2Adeletion 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 hemizygousPPP2R2Adeletions, using pharmacologic approaches that enhance PP2A/B55α activity.