Recently, the fatty acid elongation enzyme ELOVL5 was identified as a critical pro-metastatic factor in prostate cancer, required for cell growth and mitochondrial homeostasis. The fatty acid elongation reaction catalyzed by ELOVL5 utilizes malonyl-CoA as the carbon donor. Here, we demonstrate that ELOVL5 knockdown causes malonyl-CoA accumulation. Malonyl-CoA is a cellular substrate that can inhibit fatty acid β-oxidation in the mitochondria through allosteric inhibition of carnitine palmitoyltransferase 1A (CPT1A), the enzyme that controls the rate-limiting step of the long chain fatty acid β-oxidation cycle. We hypothesized that changes in malonyl-CoA abundance following ELOVL5 knockdown could influence mitochondrial β-oxidation rates in prostate cancer cells, and regulate cell viability. Accordingly, we find that ELOVL5 knockdown is associated with decreased mitochondrial β-oxidation in prostate cancer cells. Combining ELOVL5 knockdown with FASN inhibition to increase malonyl-CoA abundance endogenously enhances the effect of ELOVL5 knockdown on prostate cancer cell viability, while preventing malonyl-CoA production rescues the cells from the effect of ELOVL5 knockdown. Our findings indicate an additional role for fatty acid elongation, in the control of malonyl-CoA homeostasis, alongside its established role in the production of long-chain fatty acid species, to explain the importance of fatty acid elongation for cell viability.

最近，脂肪酸延伸酶 ELOVL5 被确定为前列腺癌的关键促转移因子，是细胞生长和线粒体稳态所必需的。 ELOVL5 催化的脂肪酸延伸反应利用丙二酰辅酶A作为碳供体。在这里，我们证明ELOVL5敲低会导致丙二酰辅酶 A 积累。丙二酰辅酶 A 是一种细胞底物，可通过肉碱棕榈酰转移酶 1A (CPT1A) 的变构抑制来抑制线粒体中的脂肪酸 β-氧化，CPT1A 是控制长链脂肪酸 β-氧化循环限速步骤的酶。我们假设ELOVL5敲低后丙二酰辅酶 A 丰度的变化可能会影响前列腺癌细胞中线粒体 β-氧化率，并调节细胞活力。因此，我们发现ELOVL5敲低与前列腺癌细胞中线粒体 β-氧化减少有关。将ELOVL5敲低与 FASN 抑制相结合，内源性地增加丙二酰辅酶 A 丰度，从而增强ELOVL5敲低对前列腺癌细胞活力的影响，同时阻止丙二酰辅酶 A 的产生，使细胞免受ELOVL5敲低的影响。我们的研究结果表明，脂肪酸延伸在控制丙二酰辅酶A稳态中发挥着额外的作用，除了其在长链脂肪酸种类生产中的既定作用之外，这也解释了脂肪酸延伸对细胞活力的重要性。