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Genes & Dev. 22 (6): 770-785

Copyright © 2008 by Cold Spring Harbor Laboratory Press.

Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma

Kimberly J. Briggs1,2, Ian M. Corcoran-Schwartz1, Wei Zhang1, Thomas Harcke1, Wendy L. Devereux1, Stephen B. Baylin1,2, Charles G. Eberhart1,3,, and D. Neil Watkins1,4

1 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, USA;
2 Graduate Training Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA;
3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

Abstract: Medulloblastoma is an embryonal tumor thought to arise from the granule cell precursors (GCPs) of the cerebellum. PATCHED (PTCH), an inhibitor of Hedgehog signaling, is the best-characterized tumor suppressor in medulloblastoma. However, <20% of medulloblastomas have mutations in PTCH. In the search for other tumor suppressors, interest has focused on the deletion events at the 17p13.3 locus, the most common genetic defect in medulloblastoma. This chromosomal region contains HYPERMETHYLATED IN CANCER 1 (HIC1), a transcriptional repressor that is a frequent target of epigenetic gene silencing in medulloblastoma. Here we use a mouse model of Ptch1 heterozygosity to reveal a critical tumor suppressor function for Hic1 in medulloblastoma. When compared with Ptch1 heterozygous mutants, compound Ptch1/Hic1 heterozygotes display a fourfold increased incidence of medulloblastoma. We show that Hic1 is a direct transcriptional repressor of Atonal Homolog 1 (Atoh1), a proneural transcription factor essential for cerebellar development, and show that ATOH1 expression is required for human medulloblastoma cell growth in vitro. Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.

Key Words: HIC1 • PTCH • ATOH1 • Math1 • medulloblastoma]

Received for publication December 7, 2007. Accepted for publication January 14, 2008.

4 Corresponding author.

E-MAIL nwatkins{at}jhmi.edu; FAX (410) 502-5742.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1640908.

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