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Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation

Abstract

Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Long-chain fatty acyl-CoA synthetases (ACSLs), a group of rate-limiting enzymes in fatty acid metabolism, catalyze the bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl-CoAs. In this study, systematical analysis of ACSLs levels and the amount of fatty acyl-CoAs illustrated that ACSL1 were significantly associated with the levels of a broad spectrum of fatty acyl-CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl-CoAs including C16:0-, C18:0-, C18:1-, and C18:2-CoA, triglycerides and lipid accumulation in cancer cells. Mechanistically, ACSL1 modulated mitochondrial respiration, β-oxidation, and ATP production through regulation of CPT1 activity. Knockdown of ACSL1 inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Our study implicates ACSL1 as playing an important role in prostate tumor progression, and provides a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer.

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Fig. 1: Correlation of ACSL1 expression with acyl-CoA levels and human prostate tumors.
Fig. 2: ACSL1 expression levels were elevated in prostate tumors.
Fig. 3: ACSL1 regulates proliferation, migration, and cell cycle of prostate cancer cells.
Fig. 4: ACSL1 regulates the biosynthesis of acyl-CoAs in prostate cancer cells.
Fig. 5: Knockdown of ACSL1 inhibits lipid accumulation in prostate cancer cells.
Fig. 6: Knockdown of ACSL1 inhibits mitochondrial respiration in prostate cancer cells.
Fig. 7: ACSL1 promotes growth of prostate xenograft tumors in vivo.
Fig. 8: Graphic summary of the mechanisms underlying ACSL1-mediated tumor progression.

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Acknowledgements

This work was supported by NIH (R01CA172495) and DOD (W81XWH-15-1-0507) to HC.

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Correspondence to Houjian Cai.

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Ma, Y., Zha, J., Yang, X. et al. Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation. Oncogene 40, 1806–1820 (2021). https://doi.org/10.1038/s41388-021-01667-y

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