In a groundbreaking study published in the prestigious journal Genes & Diseases, researchers from Chongqing Medical University and their affiliated hospitals have identified a novel metabolic regulator, 3-oxoacid CoA-transferase 1 (OXCT1), as a key suppressor of colorectal cancer liver metastasis (CRLM). This pivotal discovery unveils a previously unrecognized metabolic-epigenetic-oncogenic signaling axis that offers promising therapeutic and prognostic implications for a malignancy that remains a formidable clinical challenge worldwide.
Colorectal cancer (CRC) ranks among the leading causes of cancer morbidity and mortality globally, and metastasis to the liver significantly worsens clinical outcomes. The molecular underpinnings that drive liver metastasis have long eluded comprehensive understanding. Through integrated bioinformatics and experimental validation, the Chongqing team exploited high-throughput datasets—GSE41258, GSE68468, and GSE35834—to demonstrate a consistent pattern of markedly reduced OXCT1 expression in liver metastases compared to primary tumors and normal colon tissue. Immunohistochemical analyses further confirmed these findings in patient-derived tissue sections, linking low OXCT1 levels directly to metastatic progression.
Employing sophisticated genetic manipulation techniques, researchers used CRISPR-Cas9 to knockout OXCT1 in colorectal cancer cell lines HCT116 and RKO, which resulted in significantly enhanced migratory capacity of the cells, a hallmark of metastatic potential. Conversely, adenovirus-mediated overexpression of OXCT1 markedly impaired cell migration. These phenotypic changes were not confined to in vitro studies; in vivo models corroborated the tumor-suppressive function of OXCT1, highlighting its vital role in restricting liver colonization by colorectal cancer cells.
Delving into the regulatory mechanisms upstream of OXCT1 expression, the study identified the transcription factor YY1 as a critical modulator. Chromatin immunoprecipitation assays revealed YY1 binding to two discrete promoter regions of the OXCT1 gene (−1191 to −1197 and −1269 to −1275), orchestrating its transcriptional activity. This discovery opens new avenues for intervention at the transcriptional level to modulate OXCT1 expression in CRC.
Transcriptomic sequencing followed by Gene Set Enrichment Analysis (GSEA) pinpointed the Wnt signaling pathway—an oncogenic driver in numerous cancers—as a primary downstream target affected by OXCT1 expression. Overexpression of OXCT1 reduced both the levels and nuclear translocation of CDK8 and beta-catenin, crucial mediators of Wnt signaling. OXCT1 also disrupted the physical interaction between CDK8 and beta-catenin by destabilizing CDK8 and shortening beta-catenin’s half-life, dampening pathway activation. Pharmacological inhibition of CDK8 reversed enhanced migration induced by OXCT1 knockout, whereas CDK8 overexpression abrogated the tumor-suppressive effects of OXCT1, underscoring a finely tuned regulatory axis.
Importantly, the enzymatic activity of OXCT1, particularly mediated by its serine 226 residue, was found indispensable for its tumor-suppressive function. Metabolic analyses revealed that OXCT1 modulates ketone body catabolism, resulting in reduced intracellular acetyl-CoA levels. This metabolic shift leads to decreased histone H3 acetylation, an epigenetic modification essential for transcriptional activation of genes including CDK8. The ensuing downregulation of CDK8 undermines the integrity of the CDK8/beta-catenin complex, culminating in the suppression of oncogenic Wnt signaling and metastatic phenotypes.
Contrastingly, an enzymatic mutant of OXCT1 harboring a serine-to-asparagine substitution at position 226 (S226N) failed to reduce H3 acetylation, impair CDK8/beta-catenin signaling, or inhibit cell migration. This mutation underscored the critical requirement of OXCT1’s enzymatic capacity in mediating its anti-metastatic effects and highlighted the intersection of metabolic enzyme function with epigenetic and signaling regulation in cancer metastasis.
While this study significantly advances the understanding of CRLM pathobiology, the authors acknowledge limitations. The precise mechanisms by which YY1 modulates downstream OXCT1 effects and the broader metabolic rewiring involved remain areas for further investigation. They suggest that comprehensive metabolomic profiling in future studies may illuminate the complex interplay between ketone metabolism and epigenetic regulation in colorectal cancer progression.
In essence, this research delineates a novel metabolic-epigenetic-Wnt signaling axis where OXCT1 acts as a metabolic tumor suppressor, directly influencing the metastatic trajectory of colorectal cancer through modulation of key oncogenic pathways. The identification of the OXCT1/CDK8/beta-catenin axis not only deepens the molecular understanding of liver metastasis but also proposes new therapeutic targets with the potential to mitigate a clinically devastating phenomenon.
The integration of metabolic control and chromatin modification presents a refined paradigm of cancer regulation and highlights the metabolic plasticity cancer cells exploit for progression. Targeting enzymes like OXCT1 to restore their function or modulate associated epigenetic marks offers a promising, multifaceted approach to curb CRC metastasis and improve patient outcomes.
This study positions OXCT1 as a critical biomarker and therapeutic candidate, implicating metabolic pathways in epigenetic reprogramming that converge on oncogenic signaling networks. Such insights pave the way for development of targeted therapies that can disrupt metastatic mechanisms at multiple levels, ultimately providing hope for improved management of colorectal cancer liver metastases.
Subject of Research: Colorectal cancer liver metastasis and molecular regulatory mechanisms involving OXCT1
Article Title: Identification of OXCT1 as a Metabolic Tumor Suppressor of Colorectal Cancer Liver Metastasis via Modulation of the Metabolic-Epigenetic-Wnt Signaling Axis
News Publication Date: Not specified
Web References: http://dx.doi.org/10.1016/j.gendis.2025.101625
Image Credits: Chenhao Li, Deao Gong, Xiaoqun Shan, Kang Wu, Jiayao Yang, Rong Zhang, Ye Huang, Kai Wang, Ni Tang, Yuxi Zhu
Keywords: Colorectal cancer, Acetylation, OXCT1, Liver metastasis, Wnt signaling, CDK8, Beta-catenin, Epigenetics, Ketone metabolism
Tags: bioinformatics in cancer studiescancer cell migration and metastasisChongqing Medical University cancer studycolorectal cancer liver metastasis studyCRISPR/Cas9 in cancer researchepigenetic signaling in cancerimmunohistochemistry in cancer researchmetabolic regulator in colorectal cancerOXCT1 liver metastasis colorectal cancerprognostic markers for liver metastasistherapeutic implications of OXCT1tumor microenvironment and metastasis
