Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma.
SUFU alterations are common in human Sonic Hedgehog (SHH) subgroup medulloblastoma (MB). However, its tumorigenic mechanisms have remained elusive. Here, we report that loss of Sufu alone is unable to induce MB formation in mice, due to insufficient Gli2 activation. Simultaneous loss of Spop, an E3 ubiquitin ligase targeting Gli2, restores robust Gli2 activation and induces rapid MB formation in Sufu knockout background. We also demonstrated a tumor-promoting role of Sufu in Smo-activated MB (∼60% of human SHH MB) by maintaining robust Gli activity. Having established Gli2 activation as a key driver of SHH MB, we report a comprehensive analysis of its targetome. Furthermore, we identified Atoh1 as a target and molecular accomplice of Gli2 that activates core SHH MB signature genes in a synergistic manner. Overall, our work establishes the dual role of SUFU in SHH MB and provides mechanistic insights into transcriptional regulation underlying Gli2-mediated SHH MB tumorigenesis.
['Yin|Wen-Chi|WC|', 'Satkunendran|Thevagi|T|', 'Mo|Rong|R|', 'Morrissy|Sorana|S|', 'Zhang|Xiaoyun|X|', 'Huang|Eunice Shiao|ES|', 'Uusküla-Reimand|Liis|L|', 'Hou|Huayun|H|', 'Son|Joe Eun|JE|', 'Liu|Weifan|W|', 'Liu|Yulu C|YC|', 'Zhang|Jianing|J|', 'Parker|Jessica|J|', 'Wang|Xin|X|', 'Farooq|Hamza|H|', 'Selvadurai|Hayden|H|', 'Chen|Xin|X|', 'Ngan|Elly Sau-Wai|ES|', 'Cheng|Steven Y|SY|', 'Dirks|Peter B|PB|', 'Angers|Stephane|S|', 'Wilson|Michael D|MD|', 'Taylor|Michael D|MD|', 'Hui|Chi-Chung|CC|']
D000818:Animals D002471:Cell Transformation, Neoplastic D053823:Hedgehog Proteins D006801:Humans D008527:Medulloblastoma D051379:Mice D009687:Nuclear Proteins D012097:Repressor Proteins D000075746:Zinc Finger Protein Gli2
SUFU targetome GLI2 medulloblastoma SPOP Hedgehog signaling mouse model