College of Life Sciences, Shandong Agricultural University, Tai'an, Shandong, China.
Department of Anorectum, Qianfo Mount Hospital Affiliated to Shandong University, Ji'nan, Shandong, China.
Biochem Biophys Res Commun. 2019 Jun 11;513(4):1013-1018. doi: 10.1016/j.bbrc.2019.04.113. Epub 2019 Apr 19.
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 in Drosophila, and find that the E3 ligase dHerc4 degrades dSmo. Depletion of dherc4 increases 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 of herc4 activates 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.
G 蛋白偶联受体样跨膜蛋白 Smoothened（Smo）是 Hedgehog（Hh）信号通路中不可或缺的转导蛋白，其过度激活会导致多种人类癌症，包括非小细胞肺癌（NSCLC）。然而，目前仍不清楚调控 Smo 稳定性的机制。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 dSmo。dherc4 的缺失会增加 dSmo 蛋白并激活 Hh 信号通路。此外，我们还揭示了 HERC4 在 NSCLC 样本中下调，与 Smo 呈负相关。HERC4 在 NSCLC 细胞中与 Smo 相互作用。最后，我们发现敲低 herc4 会激活 Hh 信号通路并促进 NSCLC 细胞增殖。总之，我们的研究表明，HERC4 通过使致癌蛋白 Smo 不稳定来发挥肿瘤抑制作用，为 NSCLC 的治疗提供了一个有前途的治疗靶点。
