USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma
USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma
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USP22 通过防止 EGFR 突变型肺腺癌中泛素化介导的 EGFR 降解来促进对 EGFR-TKI 的耐药性
DOI：
10.1016/j.canlet.2018.07.002
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Hu, Jing
中科院分区：
文献类型：
--
作者：
Zhang, Huijuan;Han, Bing;Hu, Jing
作为一种新发现的去泛素化酶，泛素特异性蛋白酶 22 (USP22) 可预测个体癌症患者的治疗结果。然而，其对恶性肿瘤的临床作用及其在肺腺癌 (ADC) 中对 EGFR-TKI（表皮生长因子受体酪氨酸激酶抑制剂）耐药的作用仍然很大程度上未知。在这里，我们发现 USP22 促进细胞增殖、迁移和侵袭，并有助于 EGFR 突变肺 ADC 细胞对 EGFR-TKI 的抵抗。从机制上讲，USP22 使位于晚期内体的 EGFR 去泛素化，防止泛素化介导的 EGFR 降解，并增强 EGF 刺激后 EGFR 的回收。此外，USP22 在肺 ADC 细胞系 H1975 和 PC9 中持续激活多个 EGFR 下游信号通路，包括 STAT3、AKT/mTOR 和 MEK/ERK 通路。此外，USP22 可以稳定 EGFR 蛋白表达，这与 EGFR 突变肺 ADC 患者样本中的 USP22 表达相关。我们首次证明沉默 USP22 可在体外和体内抵消 EGFR-TKI 耐药性。我们建议 USP22 作为 EGFR-TKI 耐药肺 ADC 的潜在治疗靶点。
As a newly discovered deubiquitinating enzyme, ubiquitin-specific protease 22 (USP22) is predictive of therapeutic outcomes in individual cancer patients. However, its clinical effects on malignancy and its roles in conferring resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in lung adenocarcinoma (ADC) remain largely unknown. Here, we showed that USP22 promotes cell proliferation, migration and invasion, and contributes to resistance to EGFR-TKIs in EGFR mutant lung ADC cells. Mechanistically, USP22 deubiquitinates EGFR localized on late endosomes, prevents ubiquitination mediated EGFR degradation and enhances recycling of EGFR after EGF stimulation. Additionally, USP22 sustained the activation of multiple EGFR downstream signaling pathways, including STAT3, AKT/mTOR and MEK/ERK pathways, in lung ADC cell lines H1975 and PC9. Furthermore, USP22 stabilizes EGFR protein expression, which correlates with USP22 expression in EGFR-mutant lung ADC patient samples. We are the first to demonstrate that silencing USP22 counteracts EGFR-TKIs resistance both in vitro and in vivo. We propose USP22 as a potential therapeutic target for EGFR-TKIs-resistant lung ADC.