THEM6‐mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer

Blomme, A. et al. (2022) THEM6‐mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer. EMBO Molecular Medicine, 14(3), e14764. (doi: 10.15252/emmm.202114764) (PMID:35014179) (PMCID:PMC8899912)

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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.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK Beatson Institute core funding (C596/A17196) and CRUK core group awarded to HYL (A15151), to KB (A29799) and to SZ (A29800). DJM was supported by a CRUK EDx grant (C48702/A27603). MS is a Medical Research Council Clinical Research Fellow (MR/L017997/1). CN is the recipient of CRUK Clinical Research Fellowship (grant 300444-01). AB acknowledges the support of the Leon Fredericq Foundation and the “Centre Anti Cancereux pres l’Universite de Liege”. DG and KF acknowledge support from the EPSRC grant EP/L014165/1 that supported LJ.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Yin, Professor Huabing and Blyth, Professor Karen and Mason, Louise and Murphy, Professor Daniel and Lilla, Dr Sergio and Zanivan, Professor Sara and Mackay, Dr Gillian and Patel, Dr Rachana and Rushworth, Dr Linda and McGregor, Grace and Leung, Professor Hing and Salji, Dr Mark and Sumpton, Mr David and Kamphorst, Dr Jurre and Nixon, Mr Colin and Edwards, Professor Joanne and Ntala, Dr Chara and Markert, Dr Elke and Repiscak, Dr Peter and Mui, Mr Ernest Joseph and Mason, Miss Susan
Creator Roles:
Mui, E. J.Investigation
Mason, L.Investigation, Methodology
McGregor, G.Formal analysis, Methodology
Lilla, S.Formal analysis, Investigation, Methodology
Ntala, C.Formal analysis
Patel, R.Resources, Investigation, Methodology
Rushworth, L.Investigation
Mason, S.Methodology
Repiscak, P.Data curation, Formal analysis
Nixon, C.Methodology
Salji, M.Resources
Markert, E.Data curation, Formal analysis
Mackay, G.Methodology
Kamphorst, J.Supervision
Edwards, J.Resources, Formal analysis
Yin, H.Supervision, Methodology
Sumpton, D.Formal analysis, Investigation, Methodology
Blyth, K.Resources, Supervision
Murphy, D.Resources, Supervision
Zanivan, S.Supervision, Methodology
Leung, H.Conceptualization, Funding acquisition, Project administration, Writing – review and editing
Authors: Blomme, A., Peter, C., Mui, E., Rodriguez Blanco, G., An, N., Mason, L. M., Jamieson, L. E., McGregor, G. H., Lilla, S., Ntala, C., Patel, R., Thiry, M., Kung, S. H.Y., Leclercq, M., Ford, C. A., Rushworth, L. K., McGarry, D. J., Mason, S., Repiscak, P., Nixon, C., Salji, M. J., Markert, E., Mackay, G. M., Kamphorst, J. J., Graham, D., Faulds, K., Fazli, L., Gleave, M. E., Avezov, E., Edwards, J., Yin, H., Sumpton, D., Blyth, K., Close, P., Murphy, D. J., Zanivan, S., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Science and Engineering
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:EMBO Molecular Medicine
Publisher:EMBO Press
ISSN:1757-4684
ISSN (Online):1757-4676
Published Online:11 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in EMBO Molecular Medicine 14(3):e14764
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301742heterotypic intercellular ERBB signalling in early progression of KRAS LuAdDaniel MurphyCancer Research UK (CRUK)C48702/A27603CS - Beatson Institute for Cancer Research
170128Quantitative proteomic analysis of castrate-resistant prostate cancerHing LeungMedical Research Council (MRC)MR/L017997/1Institute of Cancer Sciences
190739In Situ Nanoparticle Assemblies for Healthcare Diagnostics and Therapy. Reference: 130479Pasquale MaffiaEngineering and Physical Sciences Research Council (EPSRC)EP/L014165/1III - Immunology