Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Wen-Chi Yin; Thevagi Satkunendran; Rong Mo; Sorana Morrissy; Xiaoyun Zhang; Eunice Shiao Huang; Liis Uusküla-Reimand; Huayun Hou; Joe Eun Son; Weifan Liu; Yulu C Liu; Jianing Zhang; Jessica Parker; Xin Wang; Hamza Farooq; Hayden Selvadurai; Xin Chen; Elly Sau-Wai Ngan; Steven Y Cheng; Peter B Dirks; Stephane Angers; Michael D Wilson; Michael D Taylor; Chi-Chung Hui

doi:10.1016/j.devcel.2018.11.015

Dual Regulatory Functions of SUFU and Targetome of GLI2 in SHH Subgroup Medulloblastoma

Dev Cell. 2019 Jan 28;48(2):167-183.e5. doi: 10.1016/j.devcel.2018.11.015. Epub 2018 Dec 13.

Authors

Wen-Chi Yin¹, Thevagi Satkunendran¹, Rong Mo², Sorana Morrissy³, Xiaoyun Zhang², Eunice Shiao Huang¹, Liis Uusküla-Reimand⁴, Huayun Hou⁵, Joe Eun Son², Weifan Liu¹, Yulu C Liu⁶, Jianing Zhang⁷, Jessica Parker¹, Xin Wang⁸, Hamza Farooq⁸, Hayden Selvadurai⁸, Xin Chen⁹, Elly Sau-Wai Ngan¹⁰, Steven Y Cheng¹¹, Peter B Dirks¹², Stephane Angers⁶, Michael D Wilson⁵, Michael D Taylor⁸, Chi-Chung Hui¹³

Affiliations

¹ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.
³ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonic Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
⁷ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Joint Institute of Genetics and Genomic Medicine, Zhejiang University and University of Toronto, Toronto, ON, Canada.
⁸ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonic Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Joint Institute of Genetics and Genomic Medicine, Zhejiang University and University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Surgery, University of Hong Kong, Hong Kong SAR, China.
¹¹ Department of developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
¹² Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Arthur and Sonic Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
¹³ Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Joint Institute of Genetics and Genomic Medicine, Zhejiang University and University of Toronto, Toronto, ON, Canada. Electronic address: cchui@sickkids.ca.

PMID: 30554998
DOI: 10.1016/j.devcel.2018.11.015

Abstract

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.

Keywords: GLI2; Hedgehog signaling; SPOP; SUFU; medulloblastoma; mouse model; targetome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Transformation, Neoplastic / genetics*
Hedgehog Proteins / genetics
Humans
Medulloblastoma / genetics
Mice
Nuclear Proteins / genetics*
Repressor Proteins / genetics*
Zinc Finger Protein Gli2 / genetics*

Substances

GLI2 protein, human
Gli2 protein, mouse
Hedgehog Proteins
Nuclear Proteins
Repressor Proteins
SUFU protein, human
Sufu protein, mouse
Zinc Finger Protein Gli2

Grants and funding

CIHR/Canada