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

• Type of Material: Article
• Authors: M. Hope Robinson, Emory University; Victor Maximov, Emory University; Shoeb Lallani, Emory University; Hamza Farooq, Hospital for Sick Children; Michael D. Taylor, Hospital for Sick Children; Renee D. Read, Emory University; Anna M. Kenney, Emory University
• Language: English
• Date: 2019-09-20
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-50088-1
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 13611
• End Page: 13611
• Grant/Funding Information: M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant; and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACRDT1113); and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada; and the Canadian Institutes of Health Research; with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.; R.D.R. is supported by the Rally Foundation for Childhood Cancer Research.; M.D.T. is supported by the NIH (R01CA148699 and R01CA159859); The Pediatric Brain Tumour Foundation; The Terry Fox Research Institute; The Canadian Institutes of Health Research; The Cure Search Foundation; b.r.a.i.n.child; Meagan’s Walk; Genome Canada; Genome BC; and the Ontario Institute for Cancer Research.; R01-NS061070 (AMK); NCI Winship Cancer Institute P30 Center Grant CA138292; M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto.
• Keywords: LSH; Science & Technology - Other Topics; SNF2-LIKE GENE; N-MYC; SNF2 FAMILY-MEMBER; PROLIFERATION; CELL-GROWTH; Multidisciplinary Sciences; NERVOUS-SYSTEM; SENESCENCE; Science & Technology; DNA METHYLATION; MOLECULAR SUBGROUPS
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology

Abstract

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.