SPOP suppresses testicular germ cell tumors progression through ubiquitination and degradation of DPPA2.

SPOP 通过 DPPA2 的泛素化和降解抑制睾丸生殖细胞肿瘤的进展。

• 影响指数: 3.322
• 发表时间: 06 2021 11
• 来源期刊: Biochem Biophys Res Commun
• DOI: 10.1016/j.bbrc.2021.04.002
• PMID: 33862460
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Wang J,Zhuang H,Zhang H,Li Q,Cao X,Lin Z,Lin T,Chen X,Ni X,Yang J,Zhao Y,Shen L,Wang H,Zhu J,Ye M,Jin X

关键词: DPPA2; Degradation; SPOP; TGCT; Ubiquitination

Mesh: Animals; Biomarkers, Tumor / metabolism; Cell Line, Tumor; Cell Proliferation; Heterografts; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Germ Cell and Embryonal / genetics metabolism pathology; Nuclear Proteins / genetics metabolism; Proteolysis; Repressor Proteins / genetics metabolism; Testicular Neoplasms / genetics metabolism pathology; Transcription Factors / metabolism; Ubiquitination; Mice

Abstract

Dysregulation of the ubiquitin-proteasome pathway is strongly associated with cancer initiation and progression. Speckle-type POZ(pox virus and zinc finger protein) protein(SPOP) is an adapter protein of CUL3-based E3 ubiquitin ligase complexes. Gene expression profiling from the Cancer Genome Atlas (TCGA) suggests that SPOP is downregulated in testicular germ cell tumors (TGCTs), but the specific contribution of this protein remains to be explored. In this study, we show that the germ line-specific factor DPPA2 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin-ligase complex. SPOP specifically binds to a SPOP-binding consensus (SBC) degron located in DPPA2 and targets DPPA2 for degradation via the ubiquitin-proteasome pathway. SPOP downregulation increases the expression of pluripotency markers OCT4 and Nanog but decreases that of early differentiation marker gene Fst. This effect is partly dependent on its activity toward DPPA2. In addition, the dysregulation of SPOP-DPPA2 axis contributes to the malignant transformation phenotypes of TGCT cells.

摘要

泛素-蛋白酶体途径的失调与癌症的发生和进展密切相关。斑点型POZ（痘病毒和锌指蛋白）蛋白（SPOP）是基于CUL3的E3泛素连接酶复合物的衔接蛋白。来自癌症基因组图谱（TCGA）的基因表达谱表明，SPOP在睾丸生殖细胞肿瘤（TGCT）中下调，但是这种蛋白质的具体贡献还有待探索。在这项研究中,我们表明，种系特异性因子DPPA2被鉴定为SPOP-CUL3-RBX1E3泛素连接酶复合物的蛋白水解底物。SPOP特异性结合位于DPPA2中的SPOP结合共有（SBC）degron，并通过泛素-蛋白酶体途径靶向DPPA2进行降解。SPOP下调增加了多能性标记OCT4和Nanog的表达，但降低了早期分化标记基因Fst的表达。这种作用部分依赖于其对DPPA2的活性。此外,SPOP-DPPA2轴的失调有助于TGCT细胞的恶性转化表型。