PXD028683

PXD028683 is an original dataset announced via ProteomeXchange.

Title	Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression
Description	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 show 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 prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the 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.
HostingRepository	PRIDE
AnnounceDate	2022-04-01
AnnouncementXML	Submission_2022-04-01_03:45:51.979.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	F Butter
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2021-09-21 10:11:19	ID requested
⏵ 1	2022-04-01 03:45:52	announced

Dataset with its publication pending

submitter keyword: LC-MS/MS

Falk Butter
contact affiliation	IMB, Ackermannweg 4, 55128 Mainz
contact email	f.butter@imb-mainz.de
lab head
F Butter
contact affiliation	Quantitative Proteomics Institute of Molecular Biology (IMB)
contact email	f.butter@imb-mainz.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD028683
     1. Label: PRIDE project
     2. Name: Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression