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Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma
Kimberly J. Briggs1,2,
Ian M. Corcoran-Schwartz1,
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
Medulloblastoma is an embryonal tumor thought to arise fromthe granule cell precursors (GCPs) of the cerebellum. PATCHED(PTCH), an inhibitor of Hedgehog signaling, is the best-characterizedtumor suppressor in medulloblastoma. However, <20% of medulloblastomashave 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 chromosomalregion contains HYPERMETHYLATED IN CANCER 1 (HIC1), a transcriptionalrepressor that is a frequent target of epigenetic gene silencingin medulloblastoma. Here we use a mouse model of Ptch1 heterozygosityto reveal a critical tumor suppressor function for Hic1 in medulloblastoma.When compared with Ptch1 heterozygous mutants, compound Ptch1/Hic1heterozygotes display a fourfold increased incidence of medulloblastoma.We show that Hic1 is a direct transcriptional repressor of AtonalHomolog 1 (Atoh1), a proneural transcription factor essentialfor cerebellar development, and show that ATOH1 expression isrequired for human medulloblastoma cell growth in vitro. Giventhat Atoh1 is also a putative target of Hh signaling, we concludethat the Hic1 and Ptch1 tumor suppressors cooperate to silenceAtoh1 expression during a critical phase in GCP differentiationin which malignant transformation may lead to medulloblastoma.