Stearate-derived very long-chain fatty acids are indispensable to tumor growth

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.

Automated summary

Reprogramming of lipid metabolism is a hallmark of cancer, but the involvement of specific fatty acids and enzymes in tumorigenesis is not well understood. This study shows that depletion of the enzyme acetyl-CoA carboxylase inhibits the synthesis and elongation of very long-chain fatty acids in human cancer cells. Deficiency of very long-chain fatty acids impairs mitochondrial morphology and makes cancer cells susceptible to oxidative stress and cell death.