AI Article Synopsis
- Overexpression of class I histone deacetylases (HDACs) in glioblastoma cells leads to increased resistance to the chemotherapy drug temozolomide (TMZ) by activating the DNA damage response (DDR).
- The study found that class I HDACs stimulate the expression of RAD18, an E3 ubiquitin ligase, which helps glioma cells survive DNA damage from TMZ by promoting lesion bypass.
- Inhibiting HDACs reduces RAD18 expression, making glioma cells more susceptible to TMZ, suggesting that targeting HDACs could be a potential therapeutic strategy to enhance treatment effectiveness against resistant glioblastoma.
Article Abstract
Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic-based therapies. Here, we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the S1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data showed that RAD18 is part of the O-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevented glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O-methylguanine-DNA methyltransferase (MGMT) overexpression abolished the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes a mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975953 | PMC |
| http://dx.doi.org/10.1038/s41419-022-04751-7 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
J. Quan and C. Ma, "DNMT1-Mediated Regulating on FBXO32 Promotes the Progression of Glioma Cells Through the Regulation of SKP1 Activity," Environmental Toxicology 39, no.
View Article and Find Full Text PDFA Journey into the Complexity of Temporo-Insular Gliomas: Case Report and Literature Review.
Curr Oncol
January 2025
Neurosurgery Departament at ISSSTE 1ero De Octubre, Mexico City 07760, Mexico.
Introduction: Temporo-insular gliomas, rare brain tumors originating from glial cells, comprise about 30% of brain tumors and vary in aggressiveness from grade I to IV. Despite advancements in neuroimaging and surgical techniques, their management remains complex due to their location near critical cognitive areas. Techniques like awake craniotomy have improved outcomes, but tumor heterogeneity and proximity to vital structures pose challenges.
View Article and Find Full Text PDFSingle-Cell RNA Sequencing Reveals LEF1-Driven Wnt Pathway Activation as a Shared Oncogenic Program in Hepatoblastoma and Medulloblastoma.
Curr Oncol
January 2025
Energy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, 75006 Paris, France.
(1) Background: Hepatoblastoma and medulloblastoma are two types of pediatric tumors with embryonic origins. Both tumor types can exhibit genetic alterations that affect the β-catenin and Wnt pathways; (2) Materials and Methods: This study used bioinformatics and integrative analysis of multi-omics data at both the tumor and single-cell levels to investigate two distinct pediatric tumors: medulloblastoma and hepatoblastoma; (3) Results: The cross-transcriptome analysis revealed a commonly regulated expression signature between hepatoblastoma and medulloblastoma tumors. Among the commonly upregulated genes, the transcription factor LEF1 was significantly expressed in both tumor types.
View Article and Find Full Text PDFUnderstanding the Immune System and Biospecimen-Based Response in Glioblastoma: A Practical Guide to Utilizing Signal Redundancy for Biomarker and Immune Signature Discovery.
Curr Oncol
December 2024
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, 9000 Rockville Pike, Building 10, CRC, Bethesda, MD 20892, USA.
Glioblastoma (GBM) is a primary central nervous system malignancy with a median survival of 15-20 months. The presence of both intra- and intertumoral heterogeneity limits understanding of biological mechanisms leading to tumor resistance, including immune escape. An attractive field of research to examine treatment resistance are immune signatures composed of cluster of differentiation (CD) markers and cytokines.
View Article and Find Full Text PDFFluorescence Lifetime Imaging of NAD(P)H in Patients' Lymphocytes: Evaluation of Efficacy of Immunotherapy.
Cells
January 2025
Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia.
Background: The wide variability in clinical responses to anti-tumor immunotherapy drives the search for personalized strategies. One of the promising approaches is drug screening using patient-derived models composed of tumor and immune cells. In this regard, the selection of an appropriate in vitro model and the choice of cellular response assay are critical for reliable predictions.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!