WSB1 promotes tumor metastasis by inducing pVHL degradation.
WSB1 promotes tumor metastasis by inducing pVHL degradation.
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DOI：
10.1101/gad.268128.115
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发表时间：
2015-11-01
影响因子：
10.5
通讯作者：
Lou Z
中科院分区：
文献类型：
--
作者：
Kim JJ;Lee SB;Jang J;Yi SY;Kim SH;Han SA;Lee JM;Tong SY;Vincelette ND;Gao B;Yin P;Evans D;Choi DW;Qin B;Liu T;Zhang H;Deng M;Jen J;Zhang J;Wang L;Lou Z
在这项研究中，Kim等人通过WSB 1的E3连接酶活性鉴定了WD重复序列和含SOCS盒的蛋白1（WSB 1）作为pVHL的新型调节剂。这些发现为理解pVHL-HIF通路在癌细胞侵袭和转移中的失调提供了重要的新见解。von Hippel-Lindau肿瘤抑制因子pVHL是靶向低氧诱导因子（HIF）的E3连接酶。VHL的突变导致HIF上调，并有助于与肿瘤进展相关的过程，如侵袭、转移和血管生成。然而，关于pVHL的转录后调控知之甚少。在这里，我们表明，WD重复和SOCS盒含蛋白1（WSB 1）是一个负调节pVHL通过WSB 1的E3连接酶活性。在机制上，WSB 1促进pVHL泛素化和蛋白酶体降解，从而在常氧和缺氧条件下稳定HIF。因此，WSB 1上调HIF-1α靶基因的表达，并通过其对pVHL的作用促进肿瘤的侵袭和转移。与此一致，WSB 1蛋白水平与pVHL水平和临床样品中的无转移生存率呈负相关。本研究揭示了pVHL调控肿瘤侵袭转移的新机制。
In this study, Kim et al. identified WD repeat and SOCS box-containing protein 1 (WSB1) as a novel regulator of pVHL through WSB1's E3 ligase activity. These findings provide important new insights into the understanding of misregulation of the pVHL–HIF pathway in cancer cell invasion and metastasis. The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α’s target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.