IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39845-z.html
   My bibliography  Save this article

Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma

Author

Listed:
  • 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
    National Clinical Research Center of Cancer)

  • Xuebin Zhang

    (Tianjin Huanhu Hospital)

  • Jingxuan Yang

    (The University of Oklahoma Health Sciences Center
    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
    National Clinical Research Center of Cancer)

  • Min Li

    (The University of Oklahoma Health Sciences Center
    The University of Oklahoma Health Sciences Center)

  • Yu Ren

    (Tianjin Medical University
    The University of Oklahoma Health Sciences Center
    The University of Oklahoma Health Sciences Center)

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.

Suggested Citation

  • 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 & Yu Ren, 2023. "Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39845-z
    DOI: 10.1038/s41467-023-39845-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39845-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-39845-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Xiangqi Meng & Yu Zhao & Bo Han & Caijun Zha & Yangong Zhang & Ziwei Li & Pengfei Wu & Tengfei Qi & Chuanlu Jiang & Yang Liu & Jinquan Cai, 2020. "Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Sergei Chuikov & Julia K. Kurash & Jonathan R. Wilson & Bing Xiao & Neil Justin & Gleb S. Ivanov & Kristine McKinney & Paul Tempst & Carol Prives & Steven J. Gamblin & Nickolai A. Barlev & Danny Reinb, 2004. "Regulation of p53 activity through lysine methylation," Nature, Nature, vol. 432(7015), pages 353-360, November.
    3. Sooryanarayana Varambally & Saravana M. Dhanasekaran & Ming Zhou & Terrence R. Barrette & Chandan Kumar-Sinha & Martin G. Sanda & Debashis Ghosh & Kenneth J. Pienta & Richard G. A. B. Sewalt & Arie P., 2002. "The polycomb group protein EZH2 is involved in progression of prostate cancer," Nature, Nature, vol. 419(6907), pages 624-629, October.
    4. Yi Bao & Gokce Oguz & Wee Chyan Lee & Puay Leng Lee & Kakaly Ghosh & Jiayao Li & Panpan Wang & Peter E. Lobie & Sidse Ehmsen & Henrik J. Ditzel & Andrea Wong & Ern Yu Tan & Soo Chin Lee & Qiang Yu, 2020. "EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    5. Barbara Oldrini & Nuria Vaquero-Siguero & Quanhua Mu & Paula Kroon & Ying Zhang & Marcos Galán-Ganga & Zhaoshi Bao & Zheng Wang & Hanjie Liu & Jason K. Sa & Junfei Zhao & Hoon Kim & Sandra Rodriguez-P, 2020. "MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yan Gu & Yanrong Chen & Lai Wei & Shuang Wu & Kaicheng Shen & Chengxiang Liu & Yan Dong & Yang Zhao & Yue Zhang & Chi Zhang & Wenling Zheng & Jiangyi He & Yunlong Wang & Yifei Li & Xiaoxin Zhao & Hong, 2021. "ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Antonio Rodriguez-Calero & John Gallon & Dilara Akhoundova & Sina Maletti & Alison Ferguson & Joanna Cyrta & Ursula Amstutz & Andrea Garofoli & Viola Paradiso & Scott A. Tomlins & Ekkehard Hewer & Ver, 2022. "Alterations in homologous recombination repair genes in prostate cancer brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Marco Bolis & Daniela Bossi & Arianna Vallerga & Valentina Ceserani & Manuela Cavalli & Daniela Impellizzieri & Laura Di Rito & Eugenio Zoni & Simone Mosole & Angela Rita Elia & Andrea Rinaldi & Ricar, 2021. "Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Nishit Goradia & Stefan Werner & Edukondalu Mullapudi & Sarah Greimeier & Lina Bergmann & Andras Lang & Haydyn Mertens & Aleksandra Węglarz & Simon Sander & Grzegorz Chojnowski & Harriet Wikman & Oliv, 2024. "Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Jiwei Zhao, 2017. "Reducing bias for maximum approximate conditional likelihood estimator with general missing data mechanism," Journal of Nonparametric Statistics, Taylor & Francis Journals, vol. 29(3), pages 577-593, July.
    7. Tian Tian & Chunjian Li & Jing Xiao & Yi Shen & Yihua Lu & Liying Jiang & Xun Zhuang & Minjie Chu, 2016. "Quantitative Assessment of the Polymorphisms in the HOTAIR lncRNA and Cancer Risk: A Meta-Analysis of 8 Case-Control Studies," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-11, March.
    8. Ayushi Verma & Akhilesh Singh & Manish Pratap Singh & Mushtaq Ahmad Nengroo & Krishan Kumar Saini & Saumya Ranjan Satrusal & Muqtada Ali Khan & Priyank Chaturvedi & Abhipsa Sinha & Sanjeev Meena & Anu, 2022. "EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    9. Debashis Ghosh & Arul Chinnaiyan, 2004. "Covariate adjustment in the analysis of microarray data from clinical studies," The University of Michigan Department of Biostatistics Working Paper Series 1030, Berkeley Electronic Press.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39845-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.