EMBO Molecular Medicine (Jan 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
- Coralie Peter
- CRUK Beatson Institute, Garscube Estate
- Ernest Mui
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate
- Giovanny Rodriguez Blanco
- CRUK Beatson Institute, Garscube Estate
- Ning An
- Laboratory of Cancer Signaling, GIGA‐Institute, University of Liège
- Louise M Mason
- School of Engineering, University of Glasgow
- Lauren E Jamieson
- Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde
- Grace H McGregor
- CRUK Beatson Institute, Garscube Estate
- Sergio Lilla
- CRUK Beatson Institute, Garscube Estate
- Chara Ntala
- CRUK Beatson Institute, Garscube Estate
- Rachana Patel
- CRUK Beatson Institute, Garscube Estate
- Marc Thiry
- GIGA‐Neurosciences, Unit of Cell and Tissue Biology, University of Liège
- Sonia H Y Kung
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia
- Marine Leclercq
- Laboratory of Cancer Signaling, GIGA‐Institute, University of Liège
- Catriona A Ford
- CRUK Beatson Institute, Garscube Estate
- Linda K Rushworth
- CRUK Beatson Institute, Garscube Estate
- David J McGarry
- CRUK Beatson Institute, Garscube Estate
- Susan Mason
- CRUK Beatson Institute, Garscube Estate
- Peter Repiscak
- CRUK Beatson Institute, Garscube Estate
- Colin Nixon
- CRUK Beatson Institute, Garscube Estate
- Mark J Salji
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate
- Elke Markert
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate
- Gillian M MacKay
- CRUK Beatson Institute, Garscube Estate
- Jurre J Kamphorst
- CRUK Beatson Institute, Garscube Estate
- Duncan Graham
- Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde
- Karen Faulds
- Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde
- Ladan Fazli
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia
- Martin E Gleave
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia
- Edward Avezov
- UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, University of Cambridge
- Joanne Edwards
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate
- Huabing Yin
- School of Engineering, University of Glasgow
- David Sumpton
- CRUK Beatson Institute, Garscube Estate
- Karen Blyth
- CRUK Beatson Institute, Garscube Estate
- Pierre Close
- Laboratory of Cancer Signaling, GIGA‐Institute, University of Liège
- Daniel J Murphy
- CRUK Beatson Institute, Garscube Estate
- Sara Zanivan
- CRUK Beatson Institute, Garscube Estate
- Hing Y Leung
- CRUK Beatson Institute, Garscube Estate
- DOI
- https://doi.org/10.15252/emmm.202114764
- Journal volume & issue
-
Vol. 14,
no. 3
pp. 1 – 21
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
