RNA, Messenger; Transcription Factors; X-Box Binding Protein 1; ERN1 protein, human; Protein Serine-Threonine Kinases; Endoribonucleases; Endoplasmic Reticulum Stress/genetics; Humans; RNA, Messenger/metabolism; Transcription Factors/metabolism; X-Box Binding Protein 1/genetics; X-Box Binding Protein 1/metabolism; Endoribonucleases/genetics; Endoribonucleases/metabolism; Lipid Metabolism/genetics; Neoplasms; Protein Serine-Threonine Kinases/genetics; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Almanza, Aitor ✱; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
Mnich, Katarzyna ✱; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
Blomme, Arnaud ; Université de Liège - ULiège > Département de pharmacie ; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
Robinson, Claire M; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
Rodriguez-Blanco, Giovanny ; CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
McGrath, Eoghan P; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
Le Gallo, Matthieu; Inserm U1242, University of Rennes, Rennes, France ; Centre de lutte contre le cancer Eugène Marquis, Rennes, France
Swinnen, Johannes V ; Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, Leuven, Belgium
Chatziioannou, Aristotelis; e-NIOS Applications PC, 25 Alexandros Pantou str., 17671, Kallithea, Greece ; Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou str, 11527, Athens, GR, Greece
Chevet, Eric ; Inserm U1242, University of Rennes, Rennes, France ; Centre de lutte contre le cancer Eugène Marquis, Rennes, France
Gorman, Adrienne M ; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland
Samali, Afshin ; Apoptosis Research Centre, National University of Ireland, Galway, H91 W2TY, Ireland. afshin.samali@nuigalway.ie ; School of Biological and Chemical Sciences, National University of Ireland, Galway, H91 W2TY, Ireland. afshin.samali@nuigalway.ie
This study utilized NUI Galway Genomics and Screening Core Facility, which is supported by funds from NUI Galway, Science Foundation Ireland, the Irish Government’s Program for Research in Third Level Institutions, Cycle 5 and the European Regional Development Fund. We also would like to thank the Metabolomics unit of the Cancer Research UK Beatson Institute, with particular thanks to Dr. David Sumpton. This work was funded by Precision Oncology Ireland, which is part-funded by the Science Foundation Ireland (SFI) Strategic Partnership Program (grant number 18/SPP/3522), EU H2020 MSCA RISE-734749 (INSPIRED), EU H2020 MSCA ITN-675448 (TRAIN-ERS) to A.M.G. and A.S., SFI Industry Fellowship to K.M. (18/IF/6247). We are grateful to the contributions of all our team members, in particular Dr. Shane Deegan, Dr. Brian Leuzzi, Dr. Mark Harvey, Xara Mastrokalou, and Bianca Pasat.This study utilized NUI Galway Genomics and Screening Core Facility, which is supported by funds from NUI Galway, Science Foundation Ireland, the Irish Government’s Program for Research in Third Level Institutions, Cycle 5 and the European Regional Development Fund. We also would like to thank the Metabolomics unit of the Cancer Research UK Beatson Institute, with particular thanks to Dr. David Sumpton. This work was funded by Precision Oncology Ireland, which is part-funded by the Science Foundation Ireland (SFI) Strategic Partnership Program (grant number 18/SPP/3522), EU H2020 MSCA RISE-734749 (INSPIRED), EU H2020 MSCA ITN-675448 (TRAIN-ERS) to A.M.G. and A.S., SFI Industry Fellowship to K.M. (18/IF/6247). We are grateful to the contributions of all our team members, in particular Dr. Shane Deegan, Dr. Brian Leuzzi, Dr. Mark Harvey, Xara Mastrokalou, and Bianca Pasat.
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