THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.
ATF4
ER stress
lipid metabolism
prostate cancer
therapy resistance
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 03 2022
07 03 2022
Historique:
revised:
13
12
2021
received:
23
06
2021
accepted:
15
12
2021
pubmed:
12
1
2022
medline:
15
3
2022
entrez:
11
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35014179
doi: 10.15252/emmm.202114764
pmc: PMC8899912
doi:
Substances chimiques
Androgen Antagonists
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14764Subventions
Organisme : Cancer Research UK
ID : C48702/A27603
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29799
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L017997/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29800
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 300444-01
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A15151
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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