Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target. [Display omitted] •ACAT1 is commonly activated by upregulated tetramerization in human cancers•Y407 phosphorylation stabilizes active ACAT1 tetramers•AH disrupts active ACAT1 tetramers and blocks tetramer reformation•ACAT1 is a promising anti-cancer target How mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) is “hijacked” to contribute to the Warburg effect in cancer remains unclear. Fan et al. demonstrate that tetrameric ACAT1 is commonly upregulated by Y407 phosphorylation in human cancer to promote tumor growth and provide a “proof of principle” suggesting tetrameric ACAT1 as an anti-cancer target.