Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma

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.[Keywords: HIC1; PTCH; ATOH1; Math1; medulloblastoma] Supplemental material is available at http://www.genesdev.org.

Atoh1, an Essential Transcription Factor in Neurogenesis and Intestinal and Inner Ear Development: Function, Regulation, and Context Dependency

“…In medullablastomas strongly expressing Atoh1, markers of differentiation such as TuJ1, p27 kip1 , NeuroD1, and Tag-1 are downregulated, whereas SHH target genes such as Gli1 and Gli2, which control the cell cycle are upregulated. This pattern of expression suggests that Atoh1 is required to maintain cells at an early stage of specification in order to provide time for clonal expansion (Briggs et al 2008;Zhao et al 2008;Ayrault et al 2010).…”

“…Several proteins have been identified that directly interact with an Atoh1 enhancer as demonstrated by chromatin immunoprecipitation, electrophoretic mobility shift assays, or luciferase activity, for example, Zic1, cdx2, Hfn1a, β-catenin, and Hic1 (Akazawa et al 1995;Ebert et al 2003;Mutoh et al 2006;Briggs et al 2008;D'Angelo et al 2010;Shi et al 2010). Atoh1, Sox2, β-catenin, Hfn1a, and Cdx2 upregulate Atoh1 expression (Helms et al 2000;Ebert et al 2003;Gazit et al 2004;Mutoh et al 2006;D'Angelo et al 2010;Shi et al 2010;Neves et al 2011).…”

“…Atoh1, Sox2, β-catenin, Hfn1a, and Cdx2 upregulate Atoh1 expression (Helms et al 2000;Ebert et al 2003;Gazit et al 2004;Mutoh et al 2006;D'Angelo et al 2010;Shi et al 2010;Neves et al 2011). Hes1, Hes5, Sox2, Hic1, Ngn1, NeuroD1, and Zic1 repress Atoh1 at the level of transcription (Akazawa et al 1995;Gowan et al 2001;Ebert et al 2003;Qian et al 2006;Briggs et al 2008;Dabdoub et al 2008;Pan et al 2009;Jahan et al 2010). Intriguingly, Sox2 has the ability to both upregulate and downregulate Atoh1 depending on context (Dabdoub et al 2008;Neves et al 2011).…”

Stox1 as a novel transcriptional suppressor of Math1 during cerebellar granule neurogenesis and medulloblastoma formation

“…Previous study showed that Neurod1, Zic1 and Hic1 are possible transcriptional suppressor of Math1 in the cerebellum. [52][53][54] It remains to be determined whether those known factors interact with Stox1 in the regulation of Math1 transcription. SHH-activated MB constitutes the most frequently detected molecular subtype of MB, therefore making SHH signaling related molecules the most promising therapeutic targets.…”

The Tumor Suppressor Gene Hypermethylated in Cancer 1 Is Transcriptionally Regulated by E2F1

“…Currently, three transcriptionally repressed HIC1 targets are known: (a) the type III NAD + -dependent histone/protein deacetylase Silent Information Regulator 2a homologue1 (SIRT1) is involved in regulating cellular senescence and longevity (7); (b) the fibroblast growth factor binding protein (8) enhances FGF-mediated biochemical and biological events specifically during blood vessel growth; and (c) the proneural transcription factor Atonal Homolog 1 (Atoh1) is essential for cerebellar growth and development (9).…”