IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38581-8.html
   My bibliography  Save this article

ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer

Author

Listed:
  • Tin-Lok Wong

    (The University of Hong Kong
    The University of Hong Kong – Shenzhen Hospital)

  • Jia-Jian Loh

    (The University of Hong Kong)

  • Shixun Lu

    (Sun Yat-Sen University Cancer Centre)

  • Helen H. N. Yan

    (Queen Mary Hospital)

  • Hoi Cheong Siu

    (Queen Mary Hospital)

  • Ren Xi

    (National University of Singapore)

  • Dessy Chan

    (Queen Mary Hospital)

  • Max J. F. Kam

    (The University of Hong Kong)

  • Lei Zhou

    (The University of Hong Kong
    The University of Hong Kong – Shenzhen Hospital)

  • Man Tong

    (The University of Hong Kong
    The University of Hong Kong – Shenzhen Hospital
    The Chinese University of Hong Kong)

  • John A. Copland

    (Mayo Clinic Florida)

  • Leilei Chen

    (National University of Singapore
    National University of Singapore)

  • Jing-Ping Yun

    (Sun Yat-Sen University Cancer Centre)

  • Suet Yi Leung

    (Queen Mary Hospital
    The University of Hong Kong)

  • Stephanie Ma

    (The University of Hong Kong
    The University of Hong Kong – Shenzhen Hospital)

Abstract

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 confers chemoresistance and self-renewal in an RNA editing-dependent manner. WES coupled with RNA-seq identify enrichment of hyper-edited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increases binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogates chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveil a potential target to circumvent chemoresistance.

Suggested Citation

  • Tin-Lok Wong & Jia-Jian Loh & Shixun Lu & Helen H. N. Yan & Hoi Cheong Siu & Ren Xi & Dessy Chan & Max J. F. Kam & Lei Zhou & Man Tong & John A. Copland & Leilei Chen & Jing-Ping Yun & Suet Yi Leung &, 2023. "ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38581-8
    DOI: 10.1038/s41467-023-38581-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38581-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-38581-8?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. Tannishtha Reya & Sean J. Morrison & Michael F. Clarke & Irving L. Weissman, 2001. "Stem cells, cancer, and cancer stem cells," Nature, Nature, vol. 414(6859), pages 105-111, November.
    2. Alexia Karen Cotte & Virginie Aires & Maxime Fredon & Emeric Limagne & Valentin Derangère & Marion Thibaudin & Etienne Humblin & Alessandra Scagliarini & Jean-Paul Pais Barros & Patrick Hillon & Franç, 2018. "Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    3. Kathrin Leppek & Gun Woo Byeon & Wipapat Kladwang & Hannah K. Wayment-Steele & Craig H. Kerr & Adele F. Xu & Do Soon Kim & Ved V. Topkar & Christian Choe & Daphna Rothschild & Gerald C. Tiu & Roger We, 2022. "Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Wenqian Hu & Thomas J. Sweet & Sangpen Chamnongpol & Kristian E. Baker & Jeff Coller, 2009. "Co-translational mRNA decay in Saccharomyces cerevisiae," Nature, Nature, vol. 461(7261), pages 225-229, September.
    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. Zeinab Tavasoli & Parviz Abdolmaleki & Seyed Javad Mowla & Faezeh Ghanati & Amir Sabet Sarvestani, 2009. "Investigation of the effects of static magnetic field on apoptosis in bone marrow stem cells of rat," Environment Systems and Decisions, Springer, vol. 29(2), pages 220-224, June.
    2. Sebastian Castillo-Hair & Stephen Fedak & Ban Wang & Johannes Linder & Kyle Havens & Michael Certo & Georg Seelig, 2024. "Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Siegmund Kimberly D. & Marjoram Paul & Shibata Darryl, 2008. "Modeling DNA Methylation in a Population of Cancer Cells," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 7(1), pages 1-23, June.
    4. Meacci, Luca & Primicerio, Mario & Buscaglia, Gustavo Carlos, 2021. "Growth of tumours with stem cells: The effect of crowding and ageing of cells," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 570(C).
    5. Shuyan Liu & Chengfei Liu & Xiaoyun Min & Yuanyuan Ji & Na Wang & Dan Liu & Jiangyi Cai & Ke Li, 2013. "Prognostic Value of Cancer Stem Cell Marker Aldehyde Dehydrogenase in Ovarian Cancer: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.
    6. Nikolay Bessonov & Guillaume Pinna & Andrey Minarsky & Annick Harel-Bellan & Nadya Morozova, 2019. "Mathematical modeling reveals the factors involved in the phenomena of cancer stem cells stabilization," PLOS ONE, Public Library of Science, vol. 14(11), pages 1-24, November.
    7. Christopher R S Banerji & Simone Severini & Carlos Caldas & Andrew E Teschendorff, 2015. "Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer," PLOS Computational Biology, Public Library of Science, vol. 11(3), pages 1-23, March.
    8. Qing Chen & Xin Zhang & Wei-Min Li & Yu-Qiang Ji & Hao-Zhe Cao & Pengsheng Zheng, 2014. "Prognostic Value of LGR5 in Colorectal Cancer: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(9), pages 1-9, September.
    9. Peter Kovacic & Ratnasamy Somanathan, 2017. "Unifying Mechanism for Nutrients as Anticancer Agents: Electron Transfer, Reactive Oxygen Species and Oxidative Stress," Global Journal of Health Science, Canadian Center of Science and Education, vol. 9(8), pages 1-66, August.
    10. Isabelle Bartram & Jonathan M Jeschke, 2019. "Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach," PLOS ONE, Public Library of Science, vol. 14(12), pages 1-12, December.
    11. Tang Peng & Ma Qinghua & Tang Zhenning & Wang Kaifa & Jiang Jun, 2011. "Long-Term Sphere Culture Cannot Maintain a High Ratio of Cancer Stem Cells: A Mathematical Model and Experiment," PLOS ONE, Public Library of Science, vol. 6(11), pages 1-6, November.
    12. N. Timurkaan & H. Eroksuz & A. Cevik & B. Karabulut, 2016. "Cutaneous leiomyosarcoma with osteoid metaplasia in a budgerigar (Melopsittacus undulatus): a case report," Veterinární medicína, Czech Academy of Agricultural Sciences, vol. 61(9), pages 533-537.
    13. Huiru Bai & Xiaoqin Liu & Meizhen Lin & Yuan Meng & Ruolan Tang & Yajing Guo & Nan Li & Michael F. Clarke & Shang Cai, 2024. "Progressive senescence programs induce intrinsic vulnerability to aging-related female breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Vincenzo Salemme & Mauro Vedelago & Alessandro Sarcinella & Federico Moietta & Alessio Piccolantonio & Enrico Moiso & Giorgia Centonze & Marta Manco & Andrea Guala & Alessia Lamolinara & Costanza Ange, 2023. "p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    15. Chahrazed Benosman & Bedr’Eddine Aïnseba & Arnaud Ducrot, 2015. "Optimization of Cytostatic Leukemia Therapy in an Advection–Reaction–Diffusion Model," Journal of Optimization Theory and Applications, Springer, vol. 167(1), pages 296-325, October.
    16. Jing Gao & Xingyu Jiang & Shumin Lei & Wenhao Cheng & Yi Lai & Min Li & Lei Yang & Peifeng Liu & Xiao-hua Chen & Min Huang & Haijun Yu & Huixiong Xu & Zhiai Xu, 2024. "A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Yuying Tan & Junjie Li & Guangyuan Zhao & Kai-Chih Huang & Horacio Cardenas & Yinu Wang & Daniela Matei & Ji-Xin Cheng, 2022. "Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Junho Lee & Jin Su Kim & Yangjin Kim, 2021. "Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies," PLOS Computational Biology, Public Library of Science, vol. 17(10), pages 1-28, October.
    19. Zhijin Tian & Dandan Shao & Linlin Tang & Zhen Li & Qian Chen & Yongxiu Song & Tao Li & Friedrich C. Simmel & Jie Song, 2024. "Circular single-stranded DNA as a programmable vector for gene regulation in cell-free protein expression systems," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    20. Octavio Martínez & M Humberto Reyes-Valdés & Luis Herrera-Estrella, 2010. "Cancer Reduces Transcriptome Specialization," PLOS ONE, Public Library of Science, vol. 5(5), pages 1-10, May.

    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_s41467-023-38581-8. 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.