Related Experiment Video
Updated: May 4, 2026
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3
Johannes Fabian1, Marco Lodrini, Ina Oehme
1Authors' Affiliations: Clinical Cooperation Unit Pediatric Oncology; Departments of Biostatistics and Tumor Genetics; Clinical Cooperation Unit Neuropathology; Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ); Departments of Neuropathology and Pediatric Hematology and Oncology, University of Heidelberg, Heidelberg; Transcriptome Analysis Laboratory, University of Goettingen, Goettingen; St. Lukas Klinik Solingen, Solingen; Department of Pediatric Hematology and Oncology; and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Abstract:
Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here, we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. Grainyhead-like 1 (GRHL1), a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome-wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN colocalized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation, and retarded xenograft growth in mice. GRHL1 knockdown in MYCN single-copy cells with high endogenous GRHL1 levels promoted colony formation. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading, and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma.
Insights
Histone deacetylase inhibitors target Grainyhead-like 1 (GRHL1) in neuroblastoma. This study reveals HDAC3 and MYCN repress GRHL1, suggesting HDAC3 inhibitors as a novel therapy for high-risk neuroblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma is a pediatric cancer with high mortality, necessitating new treatments.
- MYCN oncogene amplification is a marker for high-risk neuroblastoma.
- Epigenetic modifying drugs, like histone deacetylase (HDAC) inhibitors, offer potential therapeutic avenues.
Purpose of the Study:
- To investigate the role of Grainyhead-like 1 (GRHL1) in neuroblastoma.
- To explore the therapeutic potential of targeting HDACs, specifically HDAC3, in neuroblastoma.
- To elucidate the interplay between MYCN, HDAC3, and GRHL1 in neuroblastoma development and progression.
Main Methods:
- Genome-wide screening of neuroblastoma cells treated with HDAC inhibitors.
- Analysis of histone acetylation and gene expression at the GRHL1 promoter.
- Co-localization studies of HDAC3 and MYCN at the GRHL1 promoter.
- Correlation analysis of GRHL1 expression with patient survival and tumor markers.
- Functional studies involving GRHL1 overexpression and knockdown in neuroblastoma cell lines and xenografts.
- Genome-wide gene expression analysis to identify GRHL1-regulated genes.
Main Results:
- HDAC inhibitor treatment increased GRHL1 transcription via enhanced histone H4 acetylation at its promoter.
- HDAC3 and MYCN were found to co-localize at the GRHL1 promoter, repressing its transcription.
- High GRHL1 expression correlated with favorable patient survival and lacked MYCN amplification.
- Enforced GRHL1 expression inhibited proliferation and tumor growth in MYCN-amplified neuroblastoma models.
- GRHL1 knockdown promoted colony formation in MYCN single-copy neuroblastoma cells.
- GRHL1 regulates genes involved in neuroblastoma development, including nervous system development and proliferation.
Conclusions:
- HDAC3 plays a crucial role in MYCN-mediated repression of GRHL1 in neuroblastoma.
- Targeting HDAC3 activity and suppressing MYCN expression represent promising therapeutic strategies for high-risk neuroblastoma.
- GRHL1 acts as a tumor suppressor in neuroblastoma, with its expression inversely correlated to MYCN amplification and tumor aggressiveness.
Related Concept Videos
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,...
01:23Negative Regulator Molecules
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...
02:38The Ras Gene
Ras is a...
02:39lncRNA - Long Non-coding RNAs