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Chromatin remodeler HELLS maintains glioma stem cells through E2F3 and MYC
Guoxin Zhang, … , Petra Hamerlik, Jeremy N. Rich
Guoxin Zhang, … , Petra Hamerlik, Jeremy N. Rich
Published February 19, 2019
Citation Information: JCI Insight. 2019;4(7):e126140. https://doi.org/10.1172/jci.insight.126140.
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Research Article Oncology Stem cells

Chromatin remodeler HELLS maintains glioma stem cells through E2F3 and MYC

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Abstract

Glioblastomas, which contain stem cell–like glioblastoma stem cells (GSCs), are universally lethal cancers. While neural stem cells (NSCs) are usually quiescent, single-cell studies suggest that proliferating glioblastoma cells reside in the GSC population. Interrogating in silico glioma databases for epigenetic regulators that correlate with cell cycle regulation, we identified the chromatin remodeler HELLS as a potential target in glioblastoma. GSCs preferentially expressed HELLS compared with their differentiated tumor progeny and nonmalignant brain cells. Targeting HELLS disrupted GSC proliferation, survival, and self-renewal with induction of replication stress and DNA damage. Investigating potential molecular mechanisms downstream of HELLS revealed that HELLS interacted with the core oncogenic transcription factors, E2F3 and MYC, to regulate gene expression critical to GSC proliferation and maintenance. Supporting the interaction, HELLS expression strongly correlated with targets of E2F3 and MYC transcriptional activity in glioblastoma patients. The potential clinical significance of HELLS was reinforced by improved survival of tumor-bearing mice upon targeting HELLS and poor prognosis of glioma patients with elevated HELLS expression. Collectively, targeting HELLS may permit the functional disruption of the relatively undruggable MYC and E2F3 transcription factors and serve as a novel therapeutic paradigm for glioblastoma.

Authors

Guoxin Zhang, Zhen Dong, Briana C. Prager, Leo J.K. Kim, Qiulian Wu, Ryan C. Gimple, Xiuxing Wang, Shideng Bao, Petra Hamerlik, Jeremy N. Rich

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Figure 1

Proliferating glioma cells express HELLS.

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Proliferating glioma cells express HELLS.
(A) Correlation between mRNA e...
(A) Correlation between mRNA expression levels of chromatin regulators and G2/M cell cycle signature in glioblastoma patients. The top 20 (green) and bottom 20 (blue) epigenetic regulators are listed. HELLS is labeled in red. (B) Heatmap displaying correlations between epigenetic regulators and individual G2/M signature gene expression in glioblastoma patients. The top 20 and bottom 20 chromatin regulators are displayed. (C) RNA-seq, whole exome, and clinical phenotype data were aggregated from TCGA glioblastoma (GBM) and low-grade glioma (LGG) data set to visualize the expression patterns of top 5 and bottom 5 epigenetic regulators identified in A. “Codel,” codeletion of chromosomes 1p and 19q; PA-like, pilocytic astrocytoma–like; CIMP, glioma-CpG island methylator phenotype; LGm6-GBM, a subgroup of glioma enriched for histologic low-grade gliomas that also contains a subset of tumors with GBM-defining histologic criteria; KPS, Karnofsky performance status. (D and E) HELLS expression is enriched in SOX2+ glioblastoma cells in bulk tumor single-cell RNA-seq data sets. (D) t-Distributed stochastic neighbor embedding (t-SNE) plot of combined single-cell RNA-seq data from 4 glioblastoma tumors. Each dot represents a single cell with HELLS mRNA expression denoted by the color map. (E) Scatter plot of SOX2 and OLIG2 mRNA expression among glioblastoma tumor cells. Each dot represents a single cell with HELLS mRNA expression denoted by the color map.

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