Long-chain fatty acyl coenzyme A inhibits NME1/2 and regulates cancer metastasis

Fatty acid metabolism has well-established connections to cancer progression and metastasis. However, whether the metabolic intermediates of fatty acid metabolism regulate this process through protein-metabolite interactions remains largely unknown. Here, we investigated whether long-chain fatty acyl coenzyme A (LCFACoA), an important metabolic intermediate involved in fatty acid metabolism, could regulate cellular protein functions to affect cancer. We used a quantitative chemical proteomic approach to identify proteins that could be regulated by LCFA-CoA. This strategy identified NME1 and NME2 as potential targets regulated by LCFA-CoA. In vitro, LCFA-CoA potently inhibited NME1/2. In cells, LCFA-CoA inhibited clathrin-mediated endocytosis and cancer cell migration, processes regulated by NME1/2. In vivo, NME1, a known metastasis suppressor, is inhibited by LCFA-CoA, and its metastasis suppressor function is compromised in mouse models of breast cancer specifically under high-fat-diet conditions. Thus, inhibition of NME1 by LCFA-CoA provides a molecular mechanism linking fatty acid metabolism and cancer metastasis, demonstrating the power of the chemical proteomic approach for discovering regulatory roles of metabolites.

Automated summary

This study reveals that the metabolic intermediate LCFA-CoA regulates cancer metastasis by inhibiting NME1 and NME2, which play important roles in cellular protein functions such as clathrin-mediated endocytosis and cancer cell migration. The inhibitory effect of LCFA-CoA on NME1 compromises its metastasis suppressor function, especially under high-fat-diet conditions.