Citation Information: JCI Insight. 2019. https://doi.org/10.1172/jci.insight.126140.
Abstract
Glioblastoma represent universally lethal cancers, containing stem cell-like glioblastoma stem cells (GSCs). 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 to their differentiated tumor progeny and non-malignant 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. 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. Y. Kim, Qiulian Wu, Ryan C. Gimple, Xiuxing Wang, Shideng Bao, Petra Hamerlik, Jeremy N. Rich
