IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56458-w.html
   My bibliography  Save this article

Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism

Author

Listed:
  • Xiao-Qing Song

    (Fudan University)

  • Tian-Jian Yu

    (Fudan University)

  • Yang Ou-Yang

    (Fudan University)

  • Jia-Han Ding

    (Fudan University
    Fudan University)

  • Yi-Zhou Jiang

    (Fudan University)

  • Zhi-Ming Shao

    (Fudan University)

  • Yi Xiao

    (Fudan University)

Abstract

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

Suggested Citation

  • Xiao-Qing Song & Tian-Jian Yu & Yang Ou-Yang & Jia-Han Ding & Yi-Zhou Jiang & Zhi-Ming Shao & Yi Xiao, 2025. "Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56458-w
    DOI: 10.1038/s41467-025-56458-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56458-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56458-w?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. Shinjiro Hino & Akihisa Sakamoto & Katsuya Nagaoka & Kotaro Anan & Yuqing Wang & Shinya Mimasu & Takashi Umehara & Shigeyuki Yokoyama & Ken-ichiro Kosai & Mitsuyoshi Nakao, 2012. "FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    2. Christopher D. Steele & Ammal Abbasi & S. M. Ashiqul Islam & Amy L. Bowes & Azhar Khandekar & Kerstin Haase & Shadi Hames-Fathi & Dolapo Ajayi & Annelien Verfaillie & Pawan Dhami & Alex McLatchie & Ma, 2022. "Signatures of copy number alterations in human cancer," Nature, Nature, vol. 606(7916), pages 984-991, June.
    3. Jing Liu & Zhihao Zhao & Nasha Qiu & Quan Zhou & Guowei Wang & Haiping Jiang & Ying Piao & Zhuxian Zhou & Jianbin Tang & Youqing Shen, 2021. "Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Eric Metzger & Melanie Wissmann & Na Yin & Judith M. Müller & Robert Schneider & Antoine H. F. M. Peters & Thomas Günther & Reinhard Buettner & Roland Schüle, 2005. "LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription," Nature, Nature, vol. 437(7057), pages 436-439, September.
    5. Jeesun Kim & Anup Kumar Singh & Yoko Takata & Kevin Lin & Jianjun Shen & Yue Lu & Marc A. Kerenyi & Stuart H. Orkin & Taiping Chen, 2015. "LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    6. Katsutoshi Sato & Amol A. Padgaonkar & Stacey J. Baker & Stephen C. Cosenza & Olga Rechkoblit & D. R. C. Venkata Subbaiah & Josep Domingo-Domenech & Alison Bartkowski & Elisa R. Port & Aneel K. Aggarw, 2021. "Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease," Nature Communications, Nature, vol. 12(1), pages 1-14, 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. Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Kai Li & Xuan Yu & Yanteng Xu & Haixia Wang & Zheng Liu & Chong Wu & Xing Luo & Jiancheng Xu & Youqiang Fang & Enguo Ju & Shixian Lv & Hon Fai Chan & Yeh-Hsing Lao & Weiling He & Yu Tao & Mingqiang Li, 2025. "Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers," Nature Communications, Nature, vol. 16(1), pages 1-26, December.
    4. Pierre Murat & Guillaume Guilbaud & Julian E. Sale, 2024. "DNA replication initiation drives focal mutagenesis and rearrangements in human cancers," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Yong Yean Kim & Berkley E. Gryder & Ranuka Sinniah & Megan L. Peach & Jack F. Shern & Abdalla Abdelmaksoud & Silvia Pomella & Girma M. Woldemichael & Benjamin Z. Stanton & David Milewski & Joseph J. B, 2024. "KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Zhuo Han & Rui Wang & Pengliang Chi & Zihan Zhang & Ling Min & Haizhan Jiao & Guojin Ou & Dan Zhou & Dandan Qin & Chengpeng Xu & Zheng Gao & Qianqian Qi & Jialu Li & Yuechao Lu & Xiang Wang & Jing Che, 2024. "The subcortical maternal complex modulates the cell cycle during early mammalian embryogenesis via 14-3-3," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Feifei Xie & Shuzhen Luo & Dongbing Liu & Xiaojing Lu & Ming Wang & Xiaoxiao Liu & Fujian Jia & Yuzhi Pang & Yanying Shen & Chunling Zeng & Xinli Ma & Daoqiang Tang & Lin Tu & Linxi Yang & Yumei Cheng, 2024. "Genomic and transcriptomic landscape of human gastrointestinal stromal tumors," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Wen Hao Neo & Yiran Meng & Alba Rodriguez-Meira & Muhammad Z. H. Fadlullah & Christopher A. G. Booth & Emanuele Azzoni & Supat Thongjuea & Marella F. T. R. Bruijn & Sten Eirik W. Jacobsen & Adam J. Me, 2021. "Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    9. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Gianfranco Matrone & Sung Yun Jung & Jong Min Choi & Antrix Jain & Hon-Chiu Eastwood Leung & Kimal Rajapakshe & Cristian Coarfa & Julie Rodor & Martin A. Denvir & Andrew H. Baker & John P. Cooke, 2021. "Nuclear S-nitrosylation impacts tissue regeneration in zebrafish," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    11. Zhiren Wang & Wenpan Li & Yanhao Jiang & Jonghan Park & Karina Marie Gonzalez & Xiangmeng Wu & Qing-Yu Zhang & Jianqin Lu, 2024. "Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Long Bai & Yu Xiang & Minyue Tang & Shuangying Liu & Qingqing Chen & Qichao Chen & Min Zhang & Shan Wan & Yimiao Sang & Qingfang Li & Sisi Wang & Zhekun Li & Yang Song & Xiaoling Hu & Luna Mao & Guofa, 2023. "ALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N 6-methyladenosine methylation," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    13. Rongting Huang & Xianjie Huang & Yin Tong & Helen Y. N. Yan & Suet Yi Leung & Oliver Stegle & Yuanhua Huang, 2024. "Robust analysis of allele-specific copy number alterations from scRNA-seq data with XClone," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    14. Qingshuang Cai & Rajesh Sahu & Vanessa Ueberschlag-Pitiot & Sirine Souali-Crespo & Céline Charvet & Ilyes Silem & Félicie Cottard & Tao Ye & Fatima Taleb & Eric Metzger & Roland Schuele & Isabelle M. , 2024. "LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    15. Joseph M. Josephides & Chun-Long Chen, 2025. "Unravelling single-cell DNA replication timing dynamics using machine learning reveals heterogeneity in cancer progression," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    16. Qilin Zhang & Ziyan Xu & Rui Han & Yunzhi Wang & Zhen Ye & Jiajun Zhu & Yixin Cai & Fan Zhang & Jiangyan Zhao & Boyuan Yao & Zhaoyu Qin & Nidan Qiao & Ruofan Huang & Jinwen Feng & Yongfei Wang & Wenti, 2024. "Proteogenomic characterization of skull-base chordoma," Nature Communications, Nature, vol. 15(1), pages 1-32, December.
    17. Beatriz del Blanco & Sergio Niñerola & Ana M. Martín-González & Juan Paraíso-Luna & Minji Kim & Rafael Muñoz-Viana & Carina Racovac & Jose V. Sanchez-Mut & Yijun Ruan & Ángel Barco, 2024. "Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    18. Yong Yi & Guoqiang Wang & Wenhua Zhang & Shuhan Yu & Junjie Fei & Tingting An & Jianqiao Yi & Fengtian Li & Ting Huang & Jian Yang & Mengmeng Niu & Yang Wang & Chuan Xu & Zhi-Xiong Jim Xiao, 2025. "Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    19. Lei Tao & Yue Zhou & Xiangyu Pan & Yuan Luo & Jiahao Qiu & Xia Zhou & Zhiqian Chen & Yan Li & Lian Xu & Yang Zhou & Zeping Zuo & Chunqi Liu & Liang Wang & Xiaocong Liu & Xinyu Tian & Na Su & Zhengnan , 2023. "Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    20. Kyu Jin Song & Seunghyuk Choi & Kwoneel Kim & Hee Sang Hwang & Eunhyong Chang & Ji Soo Park & Seok Bo Shim & Seunghwan Choi & Yong Jin Heo & Woo Ju An & Dae Yeol Yang & Kyung-Cho Cho & Wonjun Ji & Cha, 2024. "Proteogenomic analysis reveals non-small cell lung cancer subtypes predicting chromosome instability, and tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-25, 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:16:y:2025:i:1:d:10.1038_s41467-025-56458-w. 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.