Upregulation of the chromatin remodeler HELLS is mediated by YAP1 in Sonic Hedgehog Medulloblastoma

Medulloblastoma is a malignant pediatric tumor that arises from neural progenitors in the cerebellum. Despite a five-year survival rate of ~70%, nearly all patients incur adverse side effects from current treatment strategies that drastically impact quality of life. Roughly one-third of medulloblast...

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Bibliographic Details
Published in:Scientific reports 2019-09, Vol.9 (1), p.13611-15, Article 13611
Main Authors: Robinson, M Hope, Maximov, Victor, Lallani, Shoeb, Farooq, Hamza, Taylor, Michael D, Read, Renee D, Kenney, Anna Marie
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adult
Animals
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cells, Cultured
Cerebellar Neoplasms - pathology
Cerebellum
Cerebellum - metabolism
Child
Chromatin
Chromatin - metabolism
Chromatin Assembly and Disassembly - genetics
DNA helicase
DNA Helicases - genetics
DNA Helicases - metabolism
DNA methylation
Epigenesis, Genetic - genetics
Epigenetics
Female
Gene expression
Hedgehog protein
Hedgehog Proteins - metabolism
Hedgehog Proteins - physiology
Humans
Male
Medulloblastoma
Medulloblastoma - genetics
Medulloblastoma - metabolism
Mice
Neural stem cells
Neural Stem Cells - metabolism
Neurons - metabolism
Pathogenicity
Patients
Progenitor cells
Quality of Life
Signal Transduction
Transcription
Transcription Factors - genetics
Transcription Factors - metabolism
Transcriptional Activation
Up-Regulation
Yes-associated protein
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Summary:Medulloblastoma is a malignant pediatric tumor that arises from neural progenitors in the cerebellum. Despite a five-year survival rate of ~70%, nearly all patients incur adverse side effects from current treatment strategies that drastically impact quality of life. Roughly one-third of medulloblastoma are driven by aberrant activation of the Sonic Hedgehog (SHH) signaling pathway. However, the scarcity of genetic mutations in medulloblastoma has led to investigation of other mechanisms contributing to cancer pathogenicity including epigenetic regulation of gene expression. Here, we show that Helicase, Lymphoid Specific (HELLS), a chromatin remodeler with epigenetic functions including DNA methylation and histone modification, is induced by Sonic Hedgehog (SHH) in SHH-dependent cerebellar progenitor cells and the developing murine cerebella. HELLS is also up-regulated in mouse and human SHH medulloblastoma. Others have shown that HELLS activity generally results in a repressive chromatin state. Our results demonstrate that increased expression of HELLS in our experimental systems is regulated by the oncogenic transcriptional regulator YAP1 downstream of Smoothened, the positive transducer of SHH signaling. Elucidation of HELLS as one of the downstream effectors of the SHH pathway may lead to novel targets for precision therapeutics with the promise of better outcomes for SHH medulloblastoma patients.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-50088-1