Kinectin1 depletion promotes EGFR degradation via the ubiquitin-proteosome system in cutaneous squamous cell carcinoma.
Kinectin1 depletion promotes EGFR degradation via the ubiquitin-proteosome system in cutaneous squamous cell carcinoma.
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DOI：
10.1038/s41419-021-04276-5
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发表时间：
2021-10-23
影响因子：
9
通讯作者：
Ding Z
中科院分区：
文献类型：
--
作者：
Ma J;Ma S;Zhang Y;Shen Y;Huang L;Lu T;Wang L;Wen Y;Ding Z
去激动素1(KTN1)通过降低表皮生长因子受体(EGFR)蛋白水平为抑制皮肤鳞状细胞癌(CSCC)的发生提供了一种潜在的策略。然而，KTN1的潜在机制仍然不清楚。在这项研究中，我们证明了KTN1基因敲除通过促进泛素-蛋白酶体系统在CSCC细胞中诱导EGFR降解，并且这种作用是肿瘤细胞特有的。KTN1基因敲除可增加CCDC40、PSMA1和ADRM1的表达，从而在体内和体外介导肿瘤抑制功能。在机制上，c-Myc直接与CCDC40的启动子区域结合，触发CCDC40-ADRM1-UCH37轴，促进EGFR去泛素化。此外，KTN1的耗尽通过加强PSMA1和ADRM1之间的竞争相互作用来抑制MET1-Ala252残基上的KTN1/ADRM1相互作用，从而加速EGFR的降解。这些结果得到了对小鼠异种移植和人类患者样本的研究的支持。总之，我们的发现为KTN1在CSCC中调节EGFR降解提供了新的机制洞察力。
Depletion of kinectin1 (KTN1) provides a potential strategy for inhibiting tumorigenesis of cutaneous squamous cell carcinoma (cSCC) via reduction of epidermal growth factor receptor (EGFR) protein levels. Yet, the underlying mechanisms of KTN1 remain obscure. In this study, we demonstrate that KTN1 knockdown induces EGFR degradation in cSCC cells by promoting the ubiquitin-proteasome system, and that this effect is tumor cell-specific. KTN1 knockdown increases the expression of CCDC40, PSMA1, and ADRM1 to mediate tumor suppressor functions in vivo and in vitro. Mechanistically, c-Myc directly binds to the promoter region of CCDC40 to trigger the CCDC40-ADRM1-UCH37 axis and promote EGFR deubiquitination. Furthermore, KTN1 depletion accelerates EGFR degradation by strengthening the competitive interaction between PSMA1 and ADRM1 to inhibit KTN1/ADRM1 interaction at residues Met1-Ala252. These results are supported by studies in mouse xenografts and human patient samples. Collectively, our findings provide novel mechanistic insight into KTN1 regulation of EGFR degradation in cSCC.