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

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 S_N1 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.Subject terms: Acetylation, Oncogenes     

Co-location of HDAC2 and Insulin Signaling Components in the Adult Mouse Hippocampus

As one part of epigenetics, histone deacetylases (HDACs) have been demonstrated to get into the neural events, including neurogenesis, synaptic plasticity, and neurodegeneration through regulating acetylation status of target proteins to influence protein function and gene expression. However, the recent studies indicated that HDAC2, a member of HDACs family, played a role in insulin signaling pathway and synaptic plasticity. Here, we are concerned about whether HDAC2 was co-located with insulin signaling components in postsynaptic glutamatergic neurons (PSGNs) of the adult mouse hippocampus using double immunofluorescence staining. The results displayed that HDAC2 was present in PSGNs marked by N-methyl-d-aspartate receptor subunit 2B, in which major components of insulin signaling pathway such as insulin receptor alpha and beta and insulin receptor substrate-1 were also involved. Accordingly, we speculate that the interaction of HDAC2 and insulin signaling system in PSGNs observed in the present study may serve as a potential mechanism in memory formation. We hope this could provide a valuable basis for understanding the roles of HDAC2 and insulin on cognitive impairment of diabetes mellitus, involved Alzheimer??s disease, which is also called type 3 diabetes recently. And this will also benefit to the treatment of insulin-related diseases in the central nervous system.