SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression.
SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression.
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DOI：
10.1016/j.molcel.2015.07.026
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发表时间：
2015-09-17
期刊：
影响因子：
16
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Gan W;Dai X;Lunardi A;Li Z;Inuzuka H;Liu P;Varmeh S;Zhang J;Cheng L;Sun Y;Asara JM;Beck AH;Huang J;Pandolfi PP;Wei W
ERG基因在大约50%的前列腺癌（PrCa）中与TMPRSS 2融合，导致其过表达。然而，这是否是PrCa中ERG升高的唯一机制目前尚不清楚。在这里，我们报告说，ERG的泛素化和降解是由Cullin 3为基础的泛素连接酶SPOP，这一途径的缺陷导致异常升高的ERG癌蛋白。具体而言，我们发现由ERG融合基因编码的截短型ERG（ΔERG）通过逃避SPOP介导的破坏而稳定，而前列腺癌相关的SPOP突变体也缺乏促进ERG泛素化。此外，我们表明，SPOP/ERG的相互作用是由CKI介导的磷酸化调制。重要的是，我们证明了DNA损伤药物，拓扑异构酶抑制剂，可以触发CKI激活，以恢复SPOP/ΔERG相互作用及其随后的降解。因此，SPOP作为一种肿瘤抑制因子，负性调节前列腺癌中ERG癌蛋白的稳定性。
The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa) resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation is governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, while prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drug, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Thus SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.