Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma
Stratifin regulates stabilization of receptor tyrosine kinases via interaction with ubiquitin-specific protease 8 in lung adenocarcinoma
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DOI：
10.1038/s41388-018-0342-9
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发表时间：
2018-10-04
期刊：
影响因子：
8
通讯作者：
Noguchi, Masayuki
中科院分区：
文献类型：
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作者：
Kim, Yunjung;Shiba-Ishii, Aya;Noguchi, Masayuki
在此之前，我们已经报道了层蛋白(SFN，14-3-3 sigma)作为一种新的癌基因，加速了肺腺癌的发生和发展。在此，下拉实验和LC-MS/MS分析表明，肺腺癌细胞中的泛素特异性蛋白水解酶8(USP8)与SFN特异性结合。USP8和SFN在人肺腺癌组织中的表达均高于正常肺组织，且USP8的表达与SFN的表达显著相关。SFN的表达与组织学亚型、病理分期和预后不良有关，而与USP8的表达无关。USP8稳定受体酪氨酸激酶(RTK)，如EGFR，并通过去泛素化MET，促进包括非小细胞肺癌在内的许多人类癌症的增殖活性。在体外，USP8与SFN结合，并共同定位于肺腺癌细胞的早期内吞体内。此外，USP8或SFN基因敲除导致肿瘤细胞增殖下调，与降解途径相关的p-EGFR或p-MET上调，泛素化RTK积聚，导致溶酶体降解。此外，突变体USP8不能与SFN结合，降低了RTK和p-STAT3的表达。我们还发现，与SFN的相互作用是USP8发挥其自身去泛素化功能和避免PP1去磷酸化的关键。我们的研究结果表明，SFN通过异常的USP8调节增强了肺腺癌中RTK的稳定性，提示SFN可能比USP8更适合作为肺腺癌的治疗靶点。
Previously we have reported that stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating the tumor initiation and progression of lung adenocarcinoma. Here, pull-down assay and LC-MS/MS analysis revealed that ubiquitin-specific protease 8 (USP8) specifically bound to SFN in lung adenocarcinoma cells. Both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and USP8 expression was significantly correlated with SFN expression. Expression of SFN, but not of USP8, was associated with histological subtype, pathological stage, and poor prognosis. USP8 stabilizes receptor tyrosine kinases (RTKs) such as EGFR and MET by deubiquitination, contributing to the proliferative activity of many human cancers including non-small cell lung cancer. In vitro, USP8 binds to SFN and they co-localize at the early endosomes in lung adenocarcinoma cells. Moreover, USP8 or SFN knockdown leads to downregulation of tumor cellular proliferation and upregulation of apoptosis, p-EGFR or p-MET, which are related to the degradation pathway, and accumulation of ubiquitinated RTKs, leading to lysosomal degradation. Additionally, mutant USP8, which is unable to bind to SFN, reduces the expression of RTKs and p-STAT3. We also found that interaction with SFN is critical for USP8 to exert its auto-deubiquitination function and avoid dephosphorylation by PP1. Our findings demonstrate that SFN enhances RTK stabilization through abnormal USP8 regulation in lung adenocarcinoma, suggesting that SFN could be a more suitable therapeutic target for lung adenocarcinoma than USP8.