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The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma
Open accessAbstract
Notwithstanding current multimodal treatment, including surgery, radiotherapy and chemotherapy with temozolomide (TMZ), median survival of glioblastoma (GBM) patients is about 14 months, due to the rapid emergence of cell clones resistant to treatment. Therefore, understanding the mechanisms underlying chemoresistance is mandatory to improve treatments' outcome. We generated TMZ resistant cells (TMZ-R) from a GBM cell line and from cancer stem cell-enriched cultures isolated from human GBMs. We demonstrated that TMZ resistance is partially reverted by "drug wash-out" suggesting the contribution of epigenetic mechanisms in drug resistance and supporting the possibility of TMZ rechallenge in GBM patients after prior drug exposure. The expression of histone lysine demethylase genes (KDMs) was increased in TMZ-R cells compared to parental cells, and TMZ resistance or restored sensitivity was mimicked by over-expressing or inactivating KDM5A. Methylation and expression of O6-methylguanine-DNA methyltransferase (MGMT) and drug efflux mechanisms were not altered in TMZ-R cells compared to parental TMZ sensitive cells. TMZ-R cells transiently acquired morphologic and molecular characteristics of differentiated tumor cells, features that were lost after drug wash-out. In conclusion, we demonstrated that treatment-induced TMZ resistance in GBM involves epigenetic mechanisms in a subset of slow-cycling and transiently partially differentiated cells that escape drug cytotoxicity, overcome G2 checkpoint and sustain clonal growth. We found that TMZ-R cells are sensitive to histone deacethylase inhibitors (HDACi) that synergize with TMZ. This strong synergism could be exploited to develop novel combined adjuvant therapies for this rapidly progressing and invariably lethal cancer.
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“Persisters are able to maintain viability under therapy but are typically slow cycling or dormant.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [55]
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Metadata
- Authors
- Banelli, B., Carra, E., Barbieri, F., Würth, R., Parodi, F., Pattarozzi, A., Carosio, R., Forlani, A., Allemanni, G., Marubbi, D., Florio, T., Daga, A., & Romani, M.
- Affiliations
- Ospedale Policlinico San Martino (IT)
- University of Genoa (IT)
- Corresponding author
- Romani, Massimo
- ORCID
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2015-11-02
- Volume
- 14
- Issue
- 21
- Pages
- 3418-3429
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- PMC
- PMC4825557
- OpenAlex
- W2257580565
- Cited by
- 135
- References
- 57
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 8 · 2023: 12 · 2022: 13 · 2021: 19 · 2020: 10 · 2019: 12 · 2018: 15 · 2017: 12 · 2016: 9
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- Compagnia di San Paolo
- Ministero della Salute (GR-2008-1143408)
- Associazione Italiana per la Ricerca sul Cancro (IG 13563)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- glioblastoma, temozolomide resistance, KDM5A, histone lysine demethylases, epigenetic drug resistance, cancer stem cells, tumor differentiation, G2 checkpoint, histone deacetylase inhibitors, chemoresistance, MGMT, drug efflux
- MeSH terms
- Temozolomide, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Cell Cycle, Cell Differentiation, Dacarbazine, Dose-Response Relationship, Drug, Drug Synergism, Genotype, Glioblastoma, Humans, Phenotype, Time Factors, Transfection, Neoplastic Stem Cells, Gene Expression Regulation, Neoplastic, Apoptosis, Antineoplastic Agents, Alkylating, Drug Resistance, Neoplasm, DNA Methylation, RNA Interference, Epigenesis, Genetic, Cell Line, Tumor, Cell Shape, Retinoblastoma-Binding Protein 2, Histone Deacetylase Inhibitors
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