Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
Pharmacol Res. 2021 Jul;169:105616. doi: 10.1016/j.phrs.2021.105616. Epub 2021 Apr 17.
Targeted therapy has become increasingly important and indispensable in cancer therapy. Cullin3-RING ligases (CRL3) serve as essential executors for regulating protein homeostasis in cancer development, highlighting that CRL3 might be promising targets in various cancer treatment. However, how to design new targeted therapies by disrupting the function of CRL3 is poorly understood. Here, we focus on the substrate adaptors of CRL3, and carry out a systematical research on the function of Kelch-like (KLHL) family proteins. We have identified twenty-four KLHL proteins with function of tumor promotion and thirteen KLHL proteins with high clinical significance on cancer therapy. Furthermore, we have clarified the novel biological function of KLHL13 as a vital factor that contributes to malignant progression in lung cancer. Taken together, our findings reveal multiple potential therapeutical targets and provide evidence for targeting CRL3 via KLHL substrate adaptors for cancer therapy.
靶向治疗在癌症治疗中变得越来越重要和不可或缺。Cullin3-RING 连接酶（CRL3）作为调节癌症发生中蛋白质平衡的重要执行者，突出表明 CRL3 可能是各种癌症治疗的有前途的靶点。然而，如何通过破坏 CRL3 的功能来设计新的靶向治疗方法还知之甚少。在这里，我们专注于 CRL3 的底物衔接子，并对 Kelch-like（KLHL）家族蛋白的功能进行系统研究。我们已经确定了 24 种具有肿瘤促进功能的 KLHL 蛋白和 13 种在癌症治疗中有高临床意义的 KLHL 蛋白。此外，我们阐明了 KLHL13 的新生物学功能，作为促进肺癌恶性进展的重要因素。总之，我们的发现揭示了多个潜在的治疗靶点，并为通过 KLHL 底物衔接子靶向 CRL3 进行癌症治疗提供了证据。
