IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42025-8.html
   My bibliography  Save this article

Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer

Author

Listed:
  • Lianhui Sun

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Yuan Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Boyu Yang

    (Capital Medical University)

  • Sijun Sun

    (Shanghai Jiao Tong University School of Medicine)

  • Pengshan Zhang

    (Shanghai Jiao Tong University School of Medicine)

  • Zai Luo

    (Shanghai Jiao Tong University School of Medicine)

  • Tingting Feng

    (Shanghai Jiao Tong University School of Medicine)

  • Zelin Cui

    (Shanghai Jiao Tong University School of Medicine)

  • Ting Zhu

    (Shanghai Jiao Tong University School of Medicine)

  • Yuming Li

    (Shanghai Jiao Tong University School of Medicine)

  • Zhengjun Qiu

    (Shanghai Jiao Tong University School of Medicine)

  • Guangjian Fan

    (Shanghai Jiao Tong University School of Medicine)

  • Chen Huang

    (Shanghai Jiao Tong University School of Medicine)

Abstract

Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m6A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.

Suggested Citation

  • Lianhui Sun & Yuan Zhang & Boyu Yang & Sijun Sun & Pengshan Zhang & Zai Luo & Tingting Feng & Zelin Cui & Ting Zhu & Yuming Li & Zhengjun Qiu & Guangjian Fan & Chen Huang, 2023. "Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42025-8
    DOI: 10.1038/s41467-023-42025-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42025-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42025-8?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. Di Zhang & Zhanyun Tang & He Huang & Guolin Zhou & Chang Cui & Yejing Weng & Wenchao Liu & Sunjoo Kim & Sangkyu Lee & Mathew Perez-Neut & Jun Ding & Daniel Czyz & Rong Hu & Zhen Ye & Maomao He & Y. Ge, 2019. "Metabolic regulation of gene expression by histone lactylation," Nature, Nature, vol. 574(7779), pages 575-580, October.
    2. Guangjian Fan & Lianhui Sun & Ling Meng & Chen Hu & Xing Wang & Zhan Shi & Congli Hu & Yang Han & Qingqing Yang & Liu Cao & Xiaohong Zhang & Yan Zhang & Xianmin Song & Shujie Xia & Baokun He & Shengpi, 2021. "The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Guangjian Fan & Lianhui Sun & Peipei Shan & Xianying Zhang & Jinliang Huan & Xiaohong Zhang & Dali Li & Tingting Wang & Tingting Wei & Xiaohong Zhang & Xiaoyang Gu & Liangfang Yao & Yang Xuan & Zhaoyu, 2015. "Loss of KLF14 triggers centrosome amplification and tumorigenesis," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    4. Lucrezia Colonna & Christopher W. Peterson & John B. Schell & Judith M. Carlson & Victor Tkachev & Melanie Brown & Alison Yu & Sowmya Reddy & Willi M. Obenza & Veronica Nelson & Patricia S. Polacino &, 2018. "Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation," Nature Communications, Nature, vol. 9(1), pages 1-15, 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. Shuangshuang Sun & Zhe Xu & Liying He & Yihui Shen & Yuqing Yan & Xubing Lv & Xujing Zhu & Wei Li & Wei-Ya Tian & Yongjun Zheng & Sen Lin & Yadong Sun & Lei Li, 2024. "Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Markus M. Rinschen & Oleg Palygin & Ashraf El-Meanawy & Xavier Domingo-Almenara & Amelia Palermo & Lashodya V. Dissanayake & Daria Golosova & Michael A. Schafroth & Carlos Guijas & Fatih Demir & Johan, 2022. "Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Fjodor Merkuri & Megan Rothstein & Marcos Simoes-Costa, 2024. "Histone lactylation couples cellular metabolism with developmental gene regulatory networks," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Chi Zhou & Wenxin Li & Zhenxing Liang & Xianrui Wu & Sijing Cheng & Jianhong Peng & Kaixuan Zeng & Weihao Li & Ping Lan & Xin Yang & Li Xiong & Ziwei Zeng & Xiaobin Zheng & Liang Huang & Wenhua Fan & , 2024. "Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Tianshi Feng & Xuemei Zhao & Ping Gu & Wah Yang & Cunchuan Wang & Qingyu Guo & Qiaoyun Long & Qing Liu & Ying Cheng & Jin Li & Cynthia Kwan Yui Cheung & Donghai Wu & Xinyu Kong & Yong Xu & Dewei Ye & , 2022. "Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Marlies Cortés & Agnese Brischetto & M. C. Martinez-Campanario & Chiara Ninfali & Verónica Domínguez & Sara Fernández & Raquel Celis & Anna Esteve-Codina & Juan J. Lozano & Julia Sidorova & Gloria Gar, 2023. "Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Hanyang Dong & Jianji Zhang & Hui Zhang & Yue Han & Congcong Lu & Chen Chen & Xiaoxia Tan & Siyu Wang & Xue Bai & Guijin Zhai & Shanshan Tian & Tao Zhang & Zhongyi Cheng & Enmin Li & Liyan Xu & Kai Zh, 2022. "YiaC and CobB regulate lysine lactylation in Escherichia coli," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Yusuke Nasu & Abhi Aggarwal & Giang N. T. Le & Camilla Trang Vo & Yuki Kambe & Xinxing Wang & Felix R. M. Beinlich & Ashley Bomin Lee & Tina R. Ram & Fangying Wang & Kelsea A. Gorzo & Yuki Kamijo & Ma, 2023. "Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Veronica L. Li & Shuke Xiao & Pascal Schlosser & Nora Scherer & Amanda L. Wiggenhorn & Jan Spaas & Alan Sheng-Hwa Tung & Edward D. Karoly & Anna Köttgen & Jonathan Z. Long, 2024. "SLC17A1/3 transporters mediate renal excretion of Lac-Phe in mice and humans," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    10. Zhenzhen Chen & Qiankun He & Tiankun Lu & Jiayi Wu & Gaoli Shi & Luyun He & Hong Zong & Benyu Liu & Pingping Zhu, 2023. "mcPGK1-dependent mitochondrial import of PGK1 promotes metabolic reprogramming and self-renewal of liver TICs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Hanjie Zhang & Yitong Zhang & Yushi Zhang & Hanyue Li & Meitong Ou & Yongkang Yu & Fan Zhang & Huijuan Yin & Zhuo Mao & Lin Mei, 2024. "Catalytic activity of violet phosphorus-based nanosystems and the role of metabolites in tumor therapy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. Han Wang & Huiying Sun & Bilin Liang & Fang Zhang & Fan Yang & Bowen Cui & Lixia Ding & Xiang Wang & Ronghua Wang & Jiaoyang Cai & Yanjing Tang & Jianan Rao & Wenting Hu & Shuang Zhao & Wenyan Wu & Xi, 2023. "Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Shan Yao & Min-Dong Xu & Ying Wang & Shen-Ting Zhao & Jin Wang & Gui-Fu Chen & Wen-Bing Chen & Jian Liu & Guo-Bin Huang & Wen-Juan Sun & Yan-Yan Zhang & Huan-Li Hou & Lei Li & Xiang-Dong Sun, 2023. "Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Ziping Niu & Chen Chen & Siyu Wang & Congcong Lu & Zhiyue Wu & Aiyuan Wang & Jing Mo & Jianji Zhang & Yanpu Han & Ye Yuan & Yingao Zhang & Yong Zang & Chaoran He & Xue Bai & Shanshan Tian & Guijin Zha, 2024. "HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    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_s41467-023-42025-8. 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.