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Cited by 36Prostate Cancer Treatment and ResearchCancer, Lipids, and MetabolismEndoplasmic Reticulum Stress and Disease

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

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Blomme, Arnaud, Peter, Coralie, Mui, Ernest, Rodriguez Blanco, Giovanny, An, Ning, Mason, Louise M, Jamieson, Lauren E, McGregor, Grace H +29 more·2022·EMBO Molecular Medicine
DOI 10.15252/emmm.202114764PMC 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.

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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., & Leung, H. Y.
Affiliations
  • Cancer Research UK Scotland Institute (GB)
  • University of Glasgow (GB)
  • University of Liège (BE)
  • University of Strathclyde (GB)
  • University of British Columbia (CA)
  • University of Cambridge (GB)
Corresponding author
  • Blomme, Arnaud
  • Leung, Hing Y
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2022-01-11
Volume
14
Issue
3
Pages
e14764-e14764
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.202114764
PMC
PMC8899912
OpenAlex
W4206378464
Cited by
36
References
2
Citations by year
2026: 3 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 7
FWCI
5.32
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, other-oa)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion, other-oa)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • ORBi (University of Liège) (submittedVersion, cc-by)
Funders
Cancer Research UK (C596/A17196, A15151, A29799, A29800, C48702/A27603)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
castration-resistant prostate cancer, androgen deprivation therapy resistance, ether lipids, endoplasmic reticulum stress response, ATF4, sterol biosynthesis, lipid metabolism reprogramming, prognostic factors, therapeutic target
MeSH terms
Androgen Antagonists, Humans, Male, Gene Expression Regulation, Neoplastic, Lipid Metabolism, Prostatic Neoplasms, Castration-Resistant

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