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 |
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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 > School 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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