Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma

Yatian Li, Zhenyue Gao, Yuhong Wang, Bo Pang, Binbin Zhang, Ruxin Hu, Yuqing Wang, Chao Liu, Xuebin Zhang, Jingxuan Yang, Mei Mei (), Yongzhi Wang (), Xuan Zhou (), Min Li () and Yu Ren ()
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Yatian Li: Tianjin Medical University
Zhenyue Gao: Tianjin Medical University
Yuhong Wang: Tianjin Medical University
Bo Pang: Capital Medical University
Binbin Zhang: Tianjin Huanhu Hospital
Ruxin Hu: Tianjin Medical University
Yuqing Wang: Tianjin Medical University
Chao Liu: Tianjin Medical University Cancer Institute & Hospital
Xuebin Zhang: Tianjin Huanhu Hospital
Jingxuan Yang: The University of Oklahoma Health Sciences Center
Mei Mei: Tianjin Medical University
Yongzhi Wang: Capital Medical University
Xuan Zhou: Tianjin Medical University Cancer Institute & Hospital
Min Li: The University of Oklahoma Health Sciences Center
Yu Ren: Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting 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 patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.

Date: 2023
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DOI: 10.1038/s41467-023-39845-z

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