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

Nov 15, 2015Cell cycle (Georgetown, Tex.)

The enzyme KDM5A helps glioblastoma resist the drug temozolomide

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Abstract

TMZ resistance in glioblastoma cells is associated with increased expression of histone lysine demethylase genes.

TMZ resistance may be partially reversible through drug wash-out, indicating a role for epigenetic mechanisms.
Increased expression of KDM genes was observed in TMZ-resistant cells compared to sensitive cells.
Over-expression or inactivation of KDM5A mimicked TMZ resistance or restored sensitivity.
No significant changes were found in the methylation and expression of MGMT or drug efflux mechanisms between resistant and sensitive cells.
TMZ-resistant cells displayed temporary characteristics of differentiated tumor cells, which were lost after drug wash-out.
Histone deacetylase inhibitors showed strong synergy with TMZ in TMZ-resistant cells, suggesting potential for novel combined therapies.

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

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