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 (LCFA-CoA), 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.