In a recent Genes & Diseases article, researchers from Chongqing Medical University and its First and Second Affiliated Hospitals identified 3-oxoacid CoA-transferase 1 (OXCT1) as a pivotal regulator of CRLM, further elucidating the mechanisms by which OXCT1 influences metastatic progression, highlighting its potential as a novel therapeutic target.

Bioinformatics and differential expression analysis of the GSE41258, GSE68468, and GSE35834 datasets, combined with IHC validation in tissue sections, showed that low OXCT1 expression is associated with liver metastasis in colorectal cancer. Furthermore, experiments on CRISPR-Cas9 OXCT1 knockout and adenovirus-mediated overexpression (AdOXCT1) in HCT116 and RKO cell lines revealed that while OXCT1 overexpression reduces migration, OXCT1 knockout enhances migration in both cell lines. These findings were subsequently validated in vivo. Additionally, the authors identified YY1 as a key upstream regulatory factor, which, upon binding to the OXCT1 promoter at −1191 to −1197 and −1269 to −1275 regions, regulates its transcription.

Transcriptomic sequencing and GSEA identified the Wnt signaling pathway as a primary target of OXCT1. OXCT1 overexpression i) suppressed the expression and nuclear translocation of both CDK8 and beta-catenin proteins, and ii) reduced their interaction by destabilizing CDK8 and shortening the half-life of beta-catenin. Furthermore, CDK8 inhibition reversed OXCT1 knockout-induced migration and Wnt activation, whereas its overexpression neutralized the tumor-suppressive effects of OXCT1. Together, these results demonstrate that OXCT1 inhibits CRLM by destabilizing the CDK8/beta-catenin complex, thereby suppressing oncogenic Wnt signaling.

The tumor-suppressive role of OXCT1 is dependent on its S226-mediated enzymatic activity. Mechanistically, OXCT1 regulates ketone body metabolism to reduce cellular acetyl-CoA levels, leading to the inhibition of histone H3 acetylation, a process essential for the transcriptional downregulation of CDK8. This downregulation subsequently destabilizes the CDK8/beta-catenin complex, suppressing oncogenic Wnt signaling and CRLM. Conversely, the S226N enzymatic mutant fails to inhibit H3 acetylation, the CDK8/beta-catenin axis, or cellular migration, establishing that OXCT1 inhibits CRLM through a distinct metabolic-epigenetic-Wnt signaling pathway.

This study acknowledges its limitations, including the role of YY1 in regulating the downstream effects of OXCT1 and insights into how OXCT1 regulates histone acetylation. Future studies using metabolomic profiling may help to elucidate how OXCT1-driven metabolic shifts govern the molecular landscape of colorectal cancer liver metastasis.

n summary, this study identified OXCT1 as a metabolic tumor suppressor that inhibits CRLM by modulating the metabolic-epigenetic-Wnt axis. The findings of this study characterize a novel crosstalk between ketone body metabolism and oncogenic signaling, positioning the OXCT1/CDK8/beta-catenin pathway as a promising therapeutic target and prognostic biomarker for CRLM.


Reference

Title of the original paper
Low expression of OXCT1 promote colorectal cancer liver metastasis by upregulating CDK8 and β-catenin via H3 acetylation

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101625

Funding Information:
Special Key Project of Chongqing Technology Innovation and Application Development, Chongqing Science and Technology Bureau, China (CSTB2023TIAD-KPX0006)


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