RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling
Pengcheng Ma, Tao An, Liang Zhu, Longlong Zhang, Huishan Wang, Biyu Ren, Bin Sun, Xia Zhou, Yan Li, Bingyu Mao
Abstract
Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule neuron progenitors (CGNPs) and its mis-regulation is linked to various disorders, including cerebellar cancer medulloblastoma (MB). We recently identified RNF220, an ubiquitin E3 ligase promoting K63-linked polyubiquitination and nuclear exportation of Glis, as a Shh/Gli regulator involved in ventral neural patterning. Here, we report that RNF220 is required for the proliferation of CGNPs and Daoy cells (a Shh-grouped MB cell line), where it works 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 comparing to Ptch1+/- mice. Furthermore, in human clinical MB samples, RNF220 expression correlated well with that of GAB1, a Shh-group MB marker. Our findings provide new insights into the epigenetic regulation of Shh signaling and identified RNF220 as a potential new diagnostic marker and therapeutic target for Shh-group MB.