Related Experiment Video
Updated: Jul 6, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma
Kimberly J Briggs1, Ian M Corcoran-Schwartz, Wei Zhang
1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 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.
Insights
Hic1 acts as a tumor suppressor in medulloblastoma by repressing Atoh1. Loss of Hic1 cooperates with Ptch1 mutations, increasing medulloblastoma incidence in mice.
Area of Science:
- Neuro-oncology
- Developmental biology
- Cancer genetics
Background:
- Medulloblastoma is a common pediatric brain tumor originating from cerebellar granule cell precursors (GCPs).
- The Hedgehog (Hh) signaling pathway, regulated by tumor suppressor PATCHED (PTCH), is crucial in medulloblastoma development.
- While PTCH mutations are found in <20% of medulloblastomas, deletions at the 17p13.3 locus, targeting HYPERMETHYLATED IN CANCER 1 (HIC1), are frequent.
Purpose of the Study:
- To investigate the role of Hic1 as a tumor suppressor in medulloblastoma.
- To explore the functional relationship between Hic1 and Ptch1 in medulloblastoma pathogenesis.
- To identify downstream targets of Hic1 involved in medulloblastoma development.
Main Methods:
- Utilized a mouse model with Ptch1 heterozygosity.
- Generated compound Ptch1/Hic1 heterozygous mutants to assess medulloblastoma incidence.
- Performed molecular analyses to determine Hic1's transcriptional targets and their role in medulloblastoma cell growth.
Main Results:
- Compound Ptch1/Hic1 heterozygotes exhibited a fourfold increase in medulloblastoma incidence compared to Ptch1 heterozygotes.
- Hic1 was identified as a direct transcriptional repressor of Atonal Homolog 1 (Atoh1), a key transcription factor for cerebellar development.
- Atoh1 expression was essential for the in vitro growth of human medulloblastoma cells.
Conclusions:
- Hic1 functions as a critical tumor suppressor in medulloblastoma.
- Hic1 and Ptch1 cooperate to regulate Atoh1 expression during GCP differentiation.
- Silencing of Atoh1 by Hic1 and Ptch1 is vital for preventing malignant transformation in GCPs, implicating Atoh1 as a potential therapeutic target.
Related Concept Videos
02:33Hedgehog Signaling Pathway
02:23Abnormal Proliferation
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...