Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation
Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation
复制标题
来自 TMPRSS2-ERG 融合体的截短 ERG 癌蛋白可抵抗 SPOP 介导的蛋白酶体降解。
DOI：
10.1016/j.molcel.2015.07.025
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发表时间：
2015-09-17
期刊：
影响因子：
16
通讯作者：
Huang, Haojie
中科院分区：
文献类型：
--
作者：
An, Jian;Ren, Shancheng;Huang, Haojie
SPOP突变和TMPRSS 2-ERG重排共同发生在高达65%的人类前列腺癌中。虽然这两个事件是相互排斥的，但不清楚它们在功能上是否相互关联。在这里，我们证明了SPOP，作为E3泛素连接酶底物结合蛋白，促进泛素化和蛋白酶体降解的野生型ERG通过识别在N端的ERG的降解决定子基序。前列腺癌相关的SPOP突变消除了SPOP介导的ERG癌蛋白降解功能。相反，大多数TMPRSS 2-ERG融合体编码N-末端截短的ERG蛋白，其由于降解决定子损伤而对SPOP介导的降解具有抗性。我们的研究结果揭示了降解抗性作为一种以前未表征的机制，有助于前列腺癌中截短的ERG蛋白的升高。他们还表明，克服ERG对SPOP介导的降解的抗性代表了治疗表达突变的SPOP或截短的ERG的前列腺癌的可行策略。
SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.