Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-50088-1
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Funding
- NCI Winship Cancer Institute P30 Center Grant [CA138292]
- NIH [R01CA148699, R01CA159859]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- b.r.a.i.n. child
- Meagan's Walk
- Genome Canada
- Genome BC
- Ontario Institute for Cancer Research
- Canadian Cancer Society Research Institute Impact grant
- SU2C Canada Cancer Stem Cell Dream Team Research Funding by the Government of Canada through Genome Canada [SU2C-AACR-DT-19-15]
- Government of Ontario
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- Rally Foundation for Childhood Cancer Research
- Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant by Canadian Institutes of Health Research [SU2C-AACRDT1113]
- Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant by the Government of Canada through Genome Canada [SU2C-AACRDT1113]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding by Canadian Institutes of Health Research [SU2C-AACR-DT-19-15]
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Medulloblastoma is a malignant pediatric tumor that arises from neural progenitors in the cerebellum. Despite a five-year survival rate of similar to 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.
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