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

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology
Biochemistry, biophysics & molecular biology

Author, co-author :

Blomme, Arnaud ; Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling

Peter, Coralie

Mui, Ernest

Rodriguez Blanco, Giovanny

An, Ning ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling

Mason, Louise M.

Jamieson, Lauren E.

McGregor, Grace H.

Lilla, Sergio

Ntala, Chara

More authors (27 more)

Language :

English

Title :

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

Publication date :

2022

Journal title :

EMBO Molecular Medicine

ISSN :

1757-4676

eISSN :

1757-4684

Publisher :

Wiley-Blackwell, United Kingdom

Pages :

e14764

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 19 January 2022

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