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

Blomme, Arnaud and Peter, Coralie and Mui, Ernest and Rodriguez Blanco, Giovanny and An, Ning and Mason, Louise M and Jamieson, Lauren E and McGregor, Grace H and Lilla, Sergio and Ntala, Chara and Patel, Rachana and Thiry, Marc and Kung, Sonia H Y and Leclercq, Marine and Ford, Catriona A and Rushworth, Linda K and McGarry, David J and Mason, Susan and Repiscak, Peter and Nixon, Colin and Salji, Mark J and Markert, Elke and MacKay, Gillian M and Kamphorst, Jurre J and Graham, Duncan and Faulds, Karen and Fazli, Ladan and Gleave, Martin E and Avezov, Edward and Edwards, Joanne and Yin, Huabing and Sumpton, David and Blyth, Karen and Close, Pierre and Murphy, Daniel J and Zanivan, Sara and Leung, Hing Y (2022) THEM6‐mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer. EMBO Molecular Medicine, 14 (3). e14764. ISSN 1757-4684 (https://doi.org/10.15252/emmm.202114764)

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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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