THEM6-mediated lipid remodelling sustains stress resistance in cancer
THEM6-mediated lipid remodelling sustains stress resistance in cancer
ABSTRACT Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated induction of ATF4. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether, our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.
Fazli Ladan、Kamphorst Jurre J.、McGregor Grace H.、Kung Sonia H. Y.、McGarry David J.、Repiscak Peter、Markert Elke、Graham Duncan、Gleave Martin E.、Mui Ernest、Ntala Chara、Thiry Marc、Ford Catriona A.、Yin Huabing、Jamieson Lauren E.、Sumpton David、Rushworth Linda K.、Blomme Arnaud、Patel Rachana、Avezov Edward、Mason Susan、Faulds Karen、Blanco Giovanny Rodriguez、Zanivan Sara、Peter Coralie、Salji Mark J.、Blyth Karen、Leung Hing Y.、MacKay Gillian M.、Lilla Sergio、Murphy Daniel J.、Edwards Joanne、Mason Louise M.、Nixon Colin、Close Pierre
Department of Urologic Sciences, Faculty of Medicine, University of British ColumbiaCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowDepartment of Urologic Sciences, Faculty of Medicine, University of British ColumbiaCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube EstateInstitute of Cancer Sciences, University of GlasgowCentre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of StrathclydeDepartment of Urologic Sciences, Faculty of Medicine, University of British ColumbiaInstitute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowGIGA-Neurosciences, Unit of Cell and Tissue Biology, University of Li¨¨geCRUK Beatson Institute, Garscube EstateSchool of Engineering, University of GlasgowCentre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of StrathclydeCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube EstateUK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, University of CambridgeCRUK Beatson Institute, Garscube EstateCentre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of StrathclydeCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube EstateInstitute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube EstateCRUK Beatson Institute, Garscube Estate||Institute of Cancer Sciences, University of GlasgowInstitute of Cancer Sciences, University of GlasgowSchool of Engineering, University of GlasgowCRUK Beatson Institute, Garscube EstateLaboratory of Cancer Signaling, GIGA-Institute, University of Li¨¨ge
肿瘤学生物化学分子生物学
Prostate cancerLipid metabolismCholesterolER stressMYC
Fazli Ladan,Kamphorst Jurre J.,McGregor Grace H.,Kung Sonia H. Y.,McGarry David J.,Repiscak Peter,Markert Elke,Graham Duncan,Gleave Martin E.,Mui Ernest,Ntala Chara,Thiry Marc,Ford Catriona A.,Yin Huabing,Jamieson Lauren E.,Sumpton David,Rushworth Linda K.,Blomme Arnaud,Patel Rachana,Avezov Edward,Mason Susan,Faulds Karen,Blanco Giovanny Rodriguez,Zanivan Sara,Peter Coralie,Salji Mark J.,Blyth Karen,Leung Hing Y.,MacKay Gillian M.,Lilla Sergio,Murphy Daniel J.,Edwards Joanne,Mason Louise M.,Nixon Colin,Close Pierre.THEM6-mediated lipid remodelling sustains stress resistance in cancer[EB/OL].(2025-03-28)[2025-05-12].https://www.biorxiv.org/content/10.1101/2021.04.04.438378.点此复制
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