Cell Death & Disease ( IF 8.1 ) Pub Date : 2023-08-03 , DOI: 10.1038/s41419-023-06025-2
Yuwei Li 1, 2 , Huishan Wang 1 , Bin Sun 3 , Guifeng Su 4 , Yu Cang 5 , Ling Zhao 6 , Shuhua Zhao 7 , Yan Li 4 , Bingyu Mao 1, 8 , Pengcheng Ma 1
|
Sonic hedgehog (Shh)-group medulloblastoma (MB) (Shh-MB) encompasses a clinically and molecularly distinct group of cancers originating from the developing nervous system with aberrant high Shh signaling as a causative driver. We recently reported that RNF220 is required for sustained high Shh signaling during Shh-MB progression; however, how high RNF220 expression is achieved in Shh-MB is still unclear. In this study, we found that the ubiquitin E3 ligases Smurf1 and Smurf2 interact with RNF220, and target it for polyubiquitination and degradation. In MB cells, knockdown or overexpression of Smurf1 or Smurf2 promotes or inhibits cell proliferation, colony formation and xenograft growth, respectively, by controlling RNF220 protein levels, and thus modulating Shh signaling. Furthermore, in clinical human MB samples, the protein levels of Smurf1 or Smurf2 were negatively correlated with those of RNF220 or GAB1, a Shh-MB marker. Overall, this study highlights the importance of the Smurf1- and Smurf2-RNF220 axes during the pathogenesis of Shh-MB and provides new therapeutic targets for Shh-MB treatment.
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
Smurf1 和 Smurf2 介导的 RNF220 多泛素化和降解抑制 Shh 组髓母细胞瘤
声波刺猬 (Shh) 组髓母细胞瘤 (MB) (Shh-MB) 涵盖一组临床和分子上独特的癌症,起源于发育中的神经系统,以异常的高 Shh 信号作为致病驱动因素。我们最近报道,在Shh-MB进展过程中,RNF220是持续高Shh信号传导所必需的;然而,Shh-MB 中 RNF220 的表达有多高仍不清楚。在这项研究中,我们发现泛素E3连接酶Smurf1和Smurf2与RNF220相互作用,并靶向其进行多泛素化和降解。在MB细胞中,Smurf1或Smurf2的敲低或过表达通过控制RNF220蛋白水平从而调节Shh信号传导分别促进或抑制细胞增殖、集落形成和异种移植物生长。此外,在临床人类MB样本中,Smurf1或Smurf2的蛋白水平与Shh-MB标记物RNF220或GAB1的蛋白水平呈负相关。总体而言,本研究强调了 Smurf1- 和 Smurf2-RNF220 轴在 Shh-MB 发病机制中的重要性,并为 Shh-MB 治疗提供了新的治疗靶点。