EMBO Molecular Medicine (Mar 2022)
THEM6‐mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer
- Arnaud Blomme,
- Coralie Peter,
- Ernest Mui,
- Giovanny Rodriguez Blanco,
- Ning An,
- Louise M Mason,
- Lauren E Jamieson,
- Grace H McGregor,
- Sergio Lilla,
- Chara Ntala,
- Rachana Patel,
- Marc Thiry,
- Sonia H Y Kung,
- Marine Leclercq,
- Catriona A Ford,
- Linda K Rushworth,
- David J McGarry,
- Susan Mason,
- Peter Repiscak,
- Colin Nixon,
- Mark J Salji,
- Elke Markert,
- Gillian M MacKay,
- Jurre J Kamphorst,
- Duncan Graham,
- Karen Faulds,
- Ladan Fazli,
- Martin E Gleave,
- Edward Avezov,
- Joanne Edwards,
- Huabing Yin,
- David Sumpton,
- Karen Blyth,
- Pierre Close,
- Daniel J Murphy,
- Sara Zanivan,
- Hing Y Leung
Affiliations
- Arnaud Blomme
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Coralie Peter
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Ernest Mui
- Institute of Cancer Sciences University of Glasgow Garscube Estate Glasgow UK
- Giovanny Rodriguez Blanco
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Ning An
- Laboratory of Cancer Signaling GIGA‐Institute University of Liège Liège Belgium
- Louise M Mason
- School of Engineering University of Glasgow Glasgow UK
- Lauren E Jamieson
- Centre for Molecular Nanometrology Department of Pure and Applied Chemistry Technology and Innovation Centre University of Strathclyde Glasgow UK
- Grace H McGregor
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Sergio Lilla
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Chara Ntala
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Rachana Patel
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Marc Thiry
- GIGA‐Neurosciences Unit of Cell and Tissue Biology University of Liège Liège Belgium
- Sonia H Y Kung
- Department of Urologic Sciences Faculty of Medicine University of British Columbia Vancouver BC Canada
- Marine Leclercq
- Laboratory of Cancer Signaling GIGA‐Institute University of Liège Liège Belgium
- Catriona A Ford
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Linda K Rushworth
- CRUK Beatson Institute Garscube Estate Glasgow UK
- David J McGarry
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Susan Mason
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Peter Repiscak
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Colin Nixon
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Mark J Salji
- Institute of Cancer Sciences University of Glasgow Garscube Estate Glasgow UK
- Elke Markert
- Institute of Cancer Sciences University of Glasgow Garscube Estate Glasgow UK
- Gillian M MacKay
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Jurre J Kamphorst
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Duncan Graham
- Centre for Molecular Nanometrology Department of Pure and Applied Chemistry Technology and Innovation Centre University of Strathclyde Glasgow UK
- Karen Faulds
- Centre for Molecular Nanometrology Department of Pure and Applied Chemistry Technology and Innovation Centre University of Strathclyde Glasgow UK
- Ladan Fazli
- Department of Urologic Sciences Faculty of Medicine University of British Columbia Vancouver BC Canada
- Martin E Gleave
- Department of Urologic Sciences Faculty of Medicine University of British Columbia Vancouver BC Canada
- Edward Avezov
- UK Dementia Research Institute at University of Cambridge Department of Clinical Neurosciences University of CambridgeCambridge UK
- Joanne Edwards
- Institute of Cancer Sciences University of Glasgow Garscube Estate Glasgow UK
- Huabing Yin
- School of Engineering University of Glasgow Glasgow UK
- David Sumpton
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Karen Blyth
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Pierre Close
- Laboratory of Cancer Signaling GIGA‐Institute University of Liège Liège Belgium
- Daniel J Murphy
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Sara Zanivan
- CRUK Beatson Institute Garscube Estate Glasgow UK
- Hing Y Leung
- CRUK Beatson Institute Garscube Estate Glasgow UK
- DOI
- https://doi.org/10.15252/emmm.202114764
- Journal volume & issue
-
Vol. 14,
no. 3
pp. n/a – n/a
Abstract
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. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane‐associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid‐mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.
Keywords