Tmod-34. Dna Helicases Helb and Atrx Maintain Glioma Stem Cells
Year: 2017
Type: conference-abstract
Abstract: Glioma stem cells (GSCs) represent highly tumorigenic, self-renewing cells that contribute to tumor invasion, angiogenesis, and therapeutic resistance. Using comparative gene expression analysis from validated GSC models, we found two DNA helicases – DNA helicase B (HELB) and ATP-dependent helicase (ATRX) – were preferentially expressed in GSCs relative to matched differentiated glioma cells (DGCs). While ATRX mutation has been associated with diffuse astrocytomas, its role in the glioma cellular hierarchy has not been investigated to date, whereas HELB has not been studied in gliomas. We confirmed the differential expression of HELB and ATRX using RT-PCR and immunoblotting of matched GSC and DGC cultures, as well as neural stem cells, with concordance in active histone marks measured by histone 3 lysine 27 acetyl (H3K27ac). Targeting either HELB or ATRX in GSCs reduced cellular proliferation, induced apoptosis, and blocked self-renewal. In contradistinction, HELB overexpression in DGCs or neural stem cells increased cellular proliferation. Supporting the potential therapeutic value of these targets, the survival of mice bearing intracranial GSCs was significantly extended upon targeting of either HELB or ATRX. Clinical significance of HELB was noted with an association with the mesenchymal transcriptional subgroup of glioblastoma and reduced survival. Collectively, these results suggest that GSCs may preferentially express helicases due to differences in proliferation and endogenous DNA damage relative to the tumor bulk, potentially informing the development of novel therapeutic targeting of therapeutically resistant glioblastoma cells.
Source: Neuro-Oncology
Institution: Cleveland Clinic
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767794459