The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma

Barbara Banelli, Elisa Carra, Federica Barbieri, Roberto Würth, Federica Parodi, Alessandra Pattarozzi, Roberta Carosio, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Tullio Florio, Antonio Daga, Massimo Romani

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3418-3429
Number of pages12
JournalCell Cycle
Volume14
Issue number21
DOIs
Publication statusPublished - 2015

Keywords

  • Cancer stem cells
  • DNA methylation
  • Epigenetic
  • Glioblastoma
  • Histone demethylase
  • KDM5A
  • Temozolomide

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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  • Cite this

    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. (2015). The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma. Cell Cycle, 14(21), 3418-3429. https://doi.org/10.1080/15384101.2015.1090063