Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

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 SN1 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 O6-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 O6-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 O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.

Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma

“…Our study provides paradigms for how ssDNA arises and is remediated by TLS in the unique setting of TMZ-treated GBM. A recent report by Hanisch et al also showed that HDAC-overexpressing gliomas become TMZ-tolerant owing to transcriptional induction of RAD18 56 .…”

Molecular markers related to patient outcome in patients with IDH-mutant astrocytomas grade 2 to 4: A systematic review

“…Counterintuitively, increased expression of the genomic protectors RAD18 and MSH2 were negatively associated with overall survival. A possible explanation could be treatment inefficacy at these higher levels of gene expression; both high expression of RAD18 and MSH2 have been correlated to temozolomide resistance in vitro [62,63]. However, a retrospective multicenter study on MSH2 protein expression in high-grade gliomas did not find any association with overall survival when correcting for IDH-mutation status [64].…”

Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma

“…A recent report by Hanisch et al also showed that HDACoverexpressing gliomas become TMZ-tolerant owing to transcriptional induction of RAD18. 52 Futile MMR of TMZ-induced O 6 mG-thymine mis-pairs activates ATR 53 , signaling a G2 checkpoint that protects from TMZ-induced lethality 54,55 . Here we show coordinate activation of CHK1 and RAD18 in response to TMZ-induced DNA damage, consistent with a common RPA/ssDNA-based activation mechanism for both ATR/CHK1 and RAD18 pathways.…”