PXD037869
PXD037869 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Lysine methylation promotes NFAT5 activation upon EGFR activation and predicts response to temozolomide |
Description | Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binds and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks TRAF6 induced K63-linked ubiquitination mediated NFAT5 lysosomal degradation and cytosol localization restriction, result in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and PDX models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation as an effective therapeutic strategy to improve TMZ response in tumors with EGFR activation. |
HostingRepository | iProX |
AnnounceDate | 2022-11-01 |
AnnouncementXML | Submission_2023-07-17_20:53:28.264.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Yatian Li |
SpeciesList | scientific name: Homo sapiens; NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | LTQ Orbitrap |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2022-10-31 23:17:23 | ID requested | |
1 | 2022-10-31 23:23:20 | announced | |
⏵ 2 | 2023-07-17 20:53:29 | announced | 2023-07-18: Update publication information. |
Publication List
Li Y, Gao Z, Wang Y, Pang B, Zhang B, Hu R, Wang Y, Liu C, Zhang X, Yang J, Mei M, Wang Y, Zhou X, Li M, Ren Y, Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma. Nat Commun, 14(1):4062(2023) [pubmed] |
Keyword List
submitter keyword: Gene regulation, Drug resistance, Lysine methylation, NFAT5, EZH2 |
Contact List
Yu Ren | |
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contact affiliation | Department of GeDepartment of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. netics, School of Basic Medical Sciences, Tianjin Medical University |
contact email | yuren0925@tmu.edu.cn |
lab head | |
Yatian Li | |
contact affiliation | Tianjin Medical University |
contact email | liyatian598522@163.com |
dataset submitter |
Full Dataset Link List
iProX dataset URI |