State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
Development. 2020 Jun 15;147(21):dev188078. doi: 10.1242/dev.188078.
Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule neuron progenitors (CGNPs) and its mis-regulation is linked to various disorders, including the cerebellar cancer medulloblastoma (MB). We recently identified RNF220, a ubiquitin E3 ligase promoting K63-linked polyubiquitylation and nuclear exportation of Gli transcription factors, as an Shh/Gli regulator involved in ventral neural patterning. Here, we report that RNF220 is required for the proliferation of CGNPs and Daoy cells (an Shh-grouped MB cell line), working as a positive regulator of Shh signaling. Mechanistic investigation demonstrated that RNF220 promotes Shh target gene expression by targeting the PRC2 component EED, and alters levels of epigenetic modification marks on Shh target promoters. We provided evidence that RNF220; Ptch1 mice showed lower spontaneous MB occurrence compared with Ptch1 mice. Furthermore, in human clinical MB samples, RNF220 expression correlated well with that of GAB1, an Shh-group MB marker. Our findings provide new insights into the epigenetic regulation of Shh signaling and identify RNF220 as a potential new diagnostic marker and therapeutic target for Shh-group MB.
声波刺猬（Shh）信号对于小脑颗粒神经元前体细胞（CGNPs）的增殖是必不可少的，其异常调节与各种疾病有关，包括小脑癌髓母细胞瘤（MB）。我们最近发现 RNF220 是一种泛素 E3 连接酶，可促进 Gli 转录因子的 K63 连接多泛素化和核输出，作为参与腹侧神经模式形成的 Shh/Gli 调节剂。在这里，我们报告 RNF220 是 CGNPs 和 Daoy 细胞（一种 Shh 组 MB 细胞系）增殖所必需的，作为 Shh 信号的正调节剂。机制研究表明，RNF220 通过靶向 PRC2 成分 EED 促进 Shh 靶基因的表达，并改变 Shh 靶启动子上的表观遗传修饰标记的水平。我们提供的证据表明，RNF220；Ptch1 小鼠比 Ptch1 小鼠的自发性 MB 发生频率更低。此外，在人类临床 MB 样本中，RNF220 的表达与 Shh 组 MB 标志物 GAB1 的表达密切相关。我们的研究结果为 Shh 信号的表观遗传调控提供了新的见解，并确定 RNF220 是 Shh 组 MB 的潜在新的诊断标志物和治疗靶点。
