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Fatty acid oxidation enzyme Δ3, Δ2-enoyl-CoA isomerase 1 (ECI1) drives aggressive tumor phenotype and predicts poor clinical outcome in prostate cancer patients

Abstract

Prostate cancer (PCa) metastases are highly enriched with genomic alterations including a gain at the 16p13.3 locus, recently shown to be associated with disease progression and poor clinical outcome. ECI1, residing at the 16p13.3 gain region, encodes Δ3, Δ2-Enoyl-CoA Delta Isomerase 1 (ECI1), a key mitochondrial fatty acid β-oxidation enzyme. Although deregulated mitochondrial fatty acid β-oxidation is known to drive PCa pathogenesis, the role of ECI1 in PCa is still unknown. We investigated the impacts of ECI1 on PCa phenotype in vitro and in vivo by modulating its expression in cell lines and assessed the clinical implications of its expression in human prostate tissue samples. In vitro, ECI1 overexpression increased PCa cell growth while ECI1 deficiency reduced its growth. ECI1 also enhanced colony formation, cell motility, and maximal mitochondrial respiratory capacity. In vivo, PCa cells stably overexpressing ECI1 injected orthotopically in nude mice formed larger prostate tumors with higher number of metastases. Immunohistochemistry analysis of the human tissue microarray representing 332 radical prostatectomy cases revealed a stronger ECI1 staining in prostate tumors compared to corresponding benign tissues. ECI1 expression varied amongst tumors and was higher in cases with 16p13.3 gain, high Gleason grade, and advanced tumor stage. ECI1 overexpression was a strong independent predictor of biochemical recurrence after adjusting for known clinicopathologic parameters (hazard ratio: 3.65, P < 0.001) or the established CAPRA-S score (hazard ratio: 3.95, P < 0.001). ECI1 overexpression was also associated with significant increased risk of distant metastasis and reduced overall survival. Overall, this study demonstrates the functional capacity of ECI1 in PCa progression and highlights the clinical implication of ECI1 as a potential target for the management of PCa.

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Fig. 1: ECI1 is overexpressed in prostate cancer at levels that varied among tumors and cell lines.
Fig. 2: ECI1 enhanced prostate cancer cells growth, colony formation, and cell motility.
Fig. 3: ECI1 increased prostate cancer cells mitochondrial spare respiratory capacity.
Fig. 4: ECI1 increased tumor growth and metastatic dissemination of prostate cancer cells orthotopically injected in nude mice.
Fig. 5: ECI1 protein is overexpressed in prostate cancer tissues and associated with adverse clinicopathologic features.
Fig. 6: High ECI1 protein expression is associated with poor clinical outcome of prostate cancer.

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Acknowledgements

Funding for this research was provided by the US Department of Defense (DoD, W81XWH-11-1-0638), Prostate Cancer Canada (D2019-2192), and the Fonds de Recherche du Québec-Santé (FRQS, Chercheur boursier) to JL. The Canadian Institutes of Health Research (CIHR) Foundation Grant to VG, CIHR System Biology and McGill Division of Urology studentships to YB, and 100 Days Across Canada Urology Studentship Program on Prostate Cancer to OK also supported the study. We are grateful to Mathieu Simard from the Small Animal Imaging Labs (SAIL) and the personnel of the Animal Resources Division of Research Institute of the McGill University Health Centre for their precious help.

Funding

US Department of Defense (DoD, W81XWH-11-1-0638), Prostate Cancer Canada (D2019-2192), the Fonds de Recherche du Québec-Santé (FRQS, Chercheur boursier) to JL. Canadian Institutes of Health Research (CIHR) Foundation Grant to VG, CIHR System Biology and McGill Division of Urology studentships to YB, and 100 Days Across Canada Urology Studentship Program on Prostate Cancer to OK.

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Conception and design: YB, KPG, EAW, JL Development of methodology: YB, KPG, EAW, JL Acquisition of data: YB, KPG, EAW, OK, EP, ES, LH, FB, MD, AA, SC, VG, JL. Analysis and interpretation of data: YB, KPG, EAW, SR, OK, FB, SC, VG, JL. Writing, review, and/or revision of the paper: YB, KPG, EAW, ES, FB, MD, AA, SC, VG, JL. Administrative, technical, or material support: ES, LH, AA Study supervision: JL.

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Correspondence to Jacques Lapointe.

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Bramhecha, Y.M., Guérard, KP., Audet-Walsh, É. et al. Fatty acid oxidation enzyme Δ3, Δ2-enoyl-CoA isomerase 1 (ECI1) drives aggressive tumor phenotype and predicts poor clinical outcome in prostate cancer patients. Oncogene 41, 2798–2810 (2022). https://doi.org/10.1038/s41388-022-02276-z

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