Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma.
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.
Briggs
Kimberly J
KJ
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Corcoran-Schwartz
Ian M
IM
Zhang
Wei
W
Harcke
Thomas
T
Devereux
Wendy L
WL
Baylin
Stephen B
SB
Eberhart
Charles G
CG
Watkins
D Neil
DN
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000473:pathology; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D008527:Medulloblastoma / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1; D037761:Sirtuins; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D056564:Sirtuin 1; D037761:Sirtuins; C500943:Atoh1 protein, mouse; C096870:Hic1 protein, mouse; C000606236:PTCH1 protein, human; C000606240:Ptch1 protein, mouse; C470545:Sirt1 protein, mouse