HERC4 exerts an anti-tumor role through destabilizing the oncoprotein Smo
HERC4 exerts an anti-tumor role through destabilizing the oncoprotein Smo
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HERC4 通过破坏癌蛋白 Smo 的稳定性发挥抗肿瘤作用
DOI：
10.1016/j.bbrc.2019.04.113
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发表时间：
2019
影响因子：
3.1
通讯作者：
Zhou Zizhang
中科院分区：
文献类型：
--
作者：
Sun Xiaohan;Sun Bing;Cui Meng;Zhou Zizhang
GPCR样跨膜蛋白Smoothens(Smo)是Hedgehog(HH)途径中不可缺少的转导蛋白，它的过度激活导致包括非小细胞肺癌(NSCLC)在内的多种人类癌症。管理Smo稳定的机制仍然难以捉摸。在这里，我们在果蝇中进行了修饰筛选，发现E3连接酶dHerc4降解了dSmo。Dherc4的缺失增加了dSmo蛋白，激活了HH途径。此外，我们还发现HERC4在非小细胞肺癌组织中表达下调，与Smo呈负相关。在NSCLC细胞中，HERC4与Smo相互作用。最后，我们发现HERC4基因的敲除激活了HH通路，促进了NSCLC细胞的增殖。综上所述，我们的研究表明，HERC4通过破坏癌蛋白Smo的稳定性而发挥肿瘤抑制作用，并为NSCLC治疗提供了一个有前景的治疗靶点。
The GPCR-like transmembrane protein Smoothened (Smo) is an indispensable transducer in Hedgehog (Hh) pathway, its hyperactivation leads to several human cancers, including non-small cell lung cancer (NSCLC). The mechanism governing Smo stability still remains elusive. Here, we perform a modifier screening inDrosophila, and find that the E3 ligase dHerc4 degrades dSmo. Depletion ofdherc4increases dSmo protein and activates Hh pathway. In addition, we reveal that HERC4 is downregulated in NSCLC samples, negative correlating with Smo. HERC4 interacts with Smo reciprocally in NSCLC cells. Finally, we show that knockdown ofherc4activates Hh pathway and promotes NSCLC cell proliferation. Taken together, our studies have demonstrated that HERC4 acts as a tumor suppressor via destabilizing the oncoprotein Smo, and provided HERC4 as a promising therapeutic target for NSCLC treatment.