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Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer

Author

Listed:
  • Aitor Almanza

    (National University of Ireland
    National University of Ireland)

  • Katarzyna Mnich

    (National University of Ireland
    National University of Ireland)

  • Arnaud Blomme

    (CRUK Beatson Institute)

  • Claire M. Robinson

    (National University of Ireland
    National University of Ireland)

  • Giovanny Rodriguez-Blanco

    (CRUK Beatson Institute)

  • Sylwia Kierszniowska

    (metaSysX GmbH)

  • Eoghan P. McGrath

    (National University of Ireland
    National University of Ireland)

  • Matthieu Gallo

    (University of Rennes
    Centre de lutte contre le cancer Eugène Marquis)

  • Eleftherios Pilalis

    (e-NIOS Applications PC)

  • Johannes V. Swinnen

    (KU Leuven Cancer Institute)

  • Aristotelis Chatziioannou

    (e-NIOS Applications PC
    Biomedical Research Foundation of the Academy of Athens)

  • Eric Chevet

    (University of Rennes
    Centre de lutte contre le cancer Eugène Marquis)

  • Adrienne M. Gorman

    (National University of Ireland
    National University of Ireland)

  • Afshin Samali

    (National University of Ireland
    National University of Ireland)

Abstract

IRE1α is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1α cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1α cleaves select mRNAs through regulated IRE1α-dependent decay (RIDD). Accumulating evidence implicates IRE1α in the regulation of lipid metabolism. However, the roles of XBP1s and RIDD in this process remain ill-defined. In this study, transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α reveals changes in lipid metabolism genes associated with accumulation of triacylglycerols (TAGs). We identify DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Inhibition of IRE1α, leads to DGAT2-dependent accumulation of TAGs in lipid droplets and sensitizes cells to nutritional stress, which is rescued by treatment with the DGAT2 inhibitor PF-06424439. Our results highlight the importance of IRE1α RIDD activity in reprograming cellular lipid metabolism.

Suggested Citation

  • Aitor Almanza & Katarzyna Mnich & Arnaud Blomme & Claire M. Robinson & Giovanny Rodriguez-Blanco & Sylwia Kierszniowska & Eoghan P. McGrath & Matthieu Gallo & Eleftherios Pilalis & Johannes V. Swinnen, 2022. "Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30159-0
    DOI: 10.1038/s41467-022-30159-0
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    References listed on IDEAS

    as
    1. Arnaud Blomme & Catriona A. Ford & Ernest Mui & Rachana Patel & Chara Ntala & Lauren E. Jamieson & Mélanie Planque & Grace H. McGregor & Paul Peixoto & Eric Hervouet & Colin Nixon & Mark Salji & Luke , 2020. "2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Susan E. Logue & Eoghan P. McGrath & Patricia Cleary & Stephanie Greene & Katarzyna Mnich & Aitor Almanza & Eric Chevet & Róisín M. Dwyer & Anup Oommen & Patrick Legembre & Florence Godey & Emma C. Ma, 2018. "Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Xi Chen & Dimitrios Iliopoulos & Qing Zhang & Qianzi Tang & Matthew B. Greenblatt & Maria Hatziapostolou & Elgene Lim & Wai Leong Tam & Min Ni & Yiwen Chen & Junhua Mai & Haifa Shen & Dorothy Z. Hu & , 2014. "XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway," Nature, Nature, vol. 508(7494), pages 103-107, April.
    4. Mengle Shao & Bo Shan & Yang Liu & Yiping Deng & Cheng Yan & Ying Wu & Ting Mao & Yifu Qiu & Yubo Zhou & Shan Jiang & Weiping Jia & Jingya Li & Jia Li & Liangyou Rui & Liu Yang & Yong Liu, 2014. "Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
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