Arginine deprivation enhances ASS1-negative glioblastoma radiosensitivity via epigenetic silencing of DNA repair genes
File(s)
Article in press
Author(s)
Type
Journal Article
Abstract
Glioblastoma (GBM) is the most aggressive form of primary brain cancer, with a poor survival. Currently, patients with GBM are treated with surgery followed by adjuvant radiotherapy and temozolomide, both of which are DNA damaging agents. However, this regimen exhibits limited efficacy, with high rates of recurrence and treatment resistance. This underscores the urgent need to identify novel and more effective therapeutic strategies or methods to enhance the efficacy of standard approaches to improve patients’ outcome and prevent recurrence. By integrating data from the Chinese Glioma Genome Atlas (CGGA) database and our own RNA sequencing analysis of 23 clinical samples, we found that low ASS1 expression correlates with increased DNA damage repair capacity and poorer prognosis in ASS1-negative GBM. Arginine deprivation via ADI-PEG20 selectively inhibited proliferation of ASS1-negative GBM cells and amplified radiotherapy-induced DNA damage, which intensified within 30 minutes and peaked at 1 hour. Mechanistically, in both ASS1-negative patient-derived tumor cells and a patient-derived xenograft (PDX) model, ADI-PEG20 downregulated DNA repair genes, namely poly ADP-ribose polymerase 1 (PARP1) and DNA ligase 1 (LIG1), at the epigenetic level by upregulating the repressive H3K27me3 histone marker. Collectively, our findings demonstrate that arginine deprivation is an effective strategy to enhance the radiosensitivity of ASS1-negative GBM and suggest that combination therapy with PARP inhibitors should be explored.
Date Issued
2026-05-30
Date Acceptance
2026-05-21
Citation
Cell Death and Disease, 2026
ISSN
2041-4889
Publisher
Nature Publishing Group
Journal / Book Title
Cell Death and Disease
Copyright Statement
© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41419-026-08920-w
Publication Status
Published online
Date Publish Online
2026-05-30