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

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.

HPGDS is a novel prognostic marker associated with lipid metabolism and aggressiveness in lung adenocarcinoma

“…Diagnostic biomarkers of LUAD and molecules should be identified for new therapeutic targets. Increased lipid uptake, storage, and lipogenesis occur in many cancers and increase tumor malignancy (29)(30)(31). Genes involved in lipid metabolism play a role in lipid metabolism reprogramming and drug resistance in tumors, making them potential targets for cancer therapy (32,33).…”

THEM6: A Novel Molecular Biomarker Predicts Tumor Microenvironment, Molecular Subtype, and Prognosis in Bladder Cancer

“…Both our study and this study have found low expression of THEM6 in some cancer tissues, but the significance of its low expression has not been studied yet. Recently, Blomme et al also found that THEM6 was highly expressed in prostate cancer and associated with poor prognosis [ 40 ]. Part of the reason for the interlaboratory variability regarding THEM6 findings and expression might be that there were heterogeneity and differences in biological behavior between different cancer types.…”

Can THEM6 targeting stop resistance to prostate cancer treatment?

“…In their study, Blomme et al (2022) show that THEM6 plays a critical role in ADT resistance by triggering ER stress response through preservation of ER membrane integrity, sterol biosynthesis, and ATF4 activation. To investigate the role of THEM6 in ADT resistance, the authors compared in vivo hormone naïve (HN) and castration‐resistant (CRPC) orthograft models of PCa by proteomics and found that THEM6 was significantly elevated in CRPC tumors.…”

“…In this issue of EMBO Mol. Med., the study by Blomme et al (2022) compared different in vivo models of ADT and identified thioesterase superfamily member 6 (THEM6) as a potentially clinically relevant protein overexpressed in CRPC. THEM (thioesterase superfamily member) are type II acyl‐CoA thioesterases (ACOTs) which are engaged in deactivation of fatty acyl‐CoA thioesters, generation of free fatty acids and CoA, regulation of intracellular fatty acid (FA) trafficking, and are an integral part of ER lipid homeostasis (Tillander et al , 2017).…”