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

M Hope Robinson,Victor Maximov,Hamza Farooq,Anna Marie Kenney,Michael D Taylor,Shoeb Lallani,Renee D Read

doi:10.1038/s41598-019-50088-1

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.

Highlights

Medulloblastoma, the most common solid pediatric tumor, is a devastating central nervous system cancer of the cerebellum that is diagnosed in over 300 children in the US each year[1]
Microarray experiments were done on cerebellar granule neuron precursors (CGNPs) in the presence or absence of Sonic Hedgehog (SHH)-N, the recombinantly produced, biologically active N-terminal fragment of SHH, which revealed genes regulated by SHH in our system
A statistically significant 5.9 ± 0.2 fold increase in Hells mRNA is observed in CGNPs with SHH-N stimulation while expression returns to basal levels with the addition of either cyclopamine or SANT-254, which both directly inhibit Smoothened (SMO) with different mechanisms of action (Fig. 1a)

Summary

Introduction

Medulloblastoma, the most common solid pediatric tumor, is a devastating central nervous system cancer of the cerebellum that is diagnosed in over 300 children in the US each year[1]. Mechanisms driving cell proliferation are often conserved between development and tumorigenesis, so it is not surprising that in SHH medulloblastoma, the same mitogenic pathway responsible for development of the cerebellum is aberrantly activated through mutations of regulators (PTCH1, SMO, SUFU) or amplification of downstream effectors (MYCN, YAP1, GLI)[3,5]. In an extension of those findings, using an SHH medulloblastoma mouse model, they demonstrated that tumors with elevated YAP1 expression grew faster and were radioresistant through the upregulation and activation of downstream components that resulted in a bypass of cell cycle checkpoints[25]. Dey et al identified a downstream component of YAP1 called Y-box protein 1 (YB1) that is upregulated in SHH stimulated CGNPs as well as in SHH medulloblastoma and is required for cell proliferation in both of these systems[27]

Methods

Results

Conclusion