Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and...

Colorectal cancer (CRC) ranks third in incidence and second in mortality worldwide. Metabolic disorders are known to be closely associated with CRC. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Previous work based on untargeted liquid chromatography identified 30 differential metabolites of CRC. Among them, only β-hydroxybutyrate (BHB) was elevated in CRC. Here, we first confirm the increased level of β-hydroxybutyrate by targeted metabolomic analysis using an independent cohort of 400 serum samples by UPLC-QQQ-MS/MS analysis. Using appropriate cell and animal models, we find that treatment with pathological levels of β-hydroxybutyrate expedites CRC proliferation and metastasis. Out of four major rate-limiting enzymes of ketolysis, only acetyl-coenzyme A acetyltransferase1 (ACAT1) expression is increased in paired human CRC tissues. These findings suggest probable clinical relevance for the functional implications of β-hydroxybutyrate in CRC. We demonstrate that β-hydroxybutyrate may exert its tumorigenic effects via regulation of ACAT1, due to induction of downstream isocitrate dehydrogenase1 (IDH1) acetylation. Genetic silencing of ACAT1 significantly suppresses the progression of CRC and abrogates the effects of β-hydroxybutyrate both in vitro and in vivo. Overall, this study suggests that targeting β-hydroxybutyrate and its major rate-limiting enzyme ACAT1 may provide a new avenue for therapeutic intervention in CRC.