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

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

Author information

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.

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

PMID:
30554998
DOI:
10.1016/j.devcel.2018.11.015
[Indexed for MEDLINE]

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