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Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1

Abstract

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.

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Fig. 1: β-Hydroxybutyrate is elevated in patients with CRC.
Fig. 2: β-Hydroxybutyrate induces CRC proliferation and invasion.
Fig. 3: ACAT1 expression is elevated in human colorectal cancer.
Fig. 4: ACAT1 promotes proliferation and metastasis in CRC.
Fig. 5: ACAT1 mediates β-hydroxybutyrate utilization to promote CRC growth and metastasis.
Fig. 6: β-Hydroxybutyrate induces acetylation of IDH1 through ACAT1.
Fig. 7: Elevated β-hydroxybutyrate in patients is possibly due to altered liver metabolism.

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Data availability

All data associated with this study are presented in the paper or the Supplementary Material. The materials that support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Xiaodong Wen from the Cellular and Molecular Biology Center of China Pharmaceutical University for advice and laboratory support. We are thankful for the grant for financial support from the National Natural Science Foundation of China (Grant Nos. 82002607 and 82072629), Key Research and Development Program of Shaanxi Province (Program No. 2022SF-215), the Open Project of State Key Laboratory of Natural Medicines, No. SKLNMKF202205 and CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-044).

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MDL and JKL conceived the original idea and designed the study. TXM contributed to the experiments and analyzed the data. FJQ and MDZ performed the experiments, in part, and analyzed the data. TXM prepared the draft of the study and revised it by MDL, JKL and JL. All authors agreed with the conclusion and approved the final study.

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Correspondence to Jiankang Li or Maode Lai.

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Mao, T., Qin, F., Zhang, M. et al. Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1. Oncogene 42, 1889–1899 (2023). https://doi.org/10.1038/s41388-023-02700-y

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