Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long-chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long-chain fatty acids (VLCFAs). Here, we show that depletion of acetyl-CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth.

中文翻译：

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硬脂酸衍生的长链脂肪酸对于肿瘤生长是不可或缺的

脂质代谢的重编程正在成为癌症的标志，但特定脂肪酸（FA）种类和相关酶在肿瘤发生中的参与仍不清楚。虽然之前的研究重点关注包括棕榈酸酯在内的长链脂肪酸 (LCFA) 与癌症的关系，但很少有人关注极长链脂肪酸 (VLCFA) 的作用。在这里，我们发现，乙酰辅酶A羧化酶（ACC1）（一种参与脂肪酸生物合成的关键酶）的消耗会抑制人类癌细胞中VLCFA的从头合成和延伸。ACC1 耗竭显着降低细胞 VLCFA，但仅轻微影响 LCFA 水平，包括可提供营养的棕榈酸酯。因此，肿瘤生长特别容易受到 VLCFA 的调节。我们进一步证明，VLCFA 缺乏会导致神经酰胺以及下游葡萄糖神经酰胺和鞘磷脂显着减少，从而损害线粒体形态并使癌细胞对氧化应激和细胞死亡敏感。综上所述，我们的研究强调，VLCFA 是癌细胞存活所选择性需要的，并揭示了抑制肿瘤生长的潜在策略。