ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.