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

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.

Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation

“…Seven of the 13 genes were highly expressed in testis, but low in other tissues. None of the signature genes except TERT was cataloged by the expert-curated Cancer Gene Census 44 (as of July 2020), although LIN9 and HELLS were recently implicated in cancer 45,46 . Mutations in HELLS, a gene encoding a lymphoidspecific helicase, cause the centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder associated with short telomeres 47 .…”

HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma

“…Abnormal epigenetic regulation related to histone modifications have been recently reported in SHH MB (Robinson et al 2019).…”

The Role of Neurodevelopmental Pathways in Brain Tumors

“…In medulloblastoma, YAP1 is significantly amplified and upregulated in SHH-activated subtypes and mediates SHH-driven NPC proliferation ( Fernandez et al, 2009 ). More recently, studies have shown that YAP1 expression leads to upregulation of chromatin remodeler helicase, lymphoid specific (HELLS) in SHH-activated medulloblastoma and is activated downstream of SHH pathway activation through SMO, a positive transducer of SHH signaling ( Robinson et al, 2019 ).…”