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

TL;DR

Low OXCT1 levels promote colorectal cancer spreading to the liver by boosting CDK8 and β-catenin through H3 acetylation, offering new therapeutic targets.

Contribution

Identifies OXCT1 as a tumor suppressor in colorectal liver metastasis and reveals its regulatory mechanism via H3 acetylation and Wnt signaling.

Findings

Low OXCT1 expression enhances tumor migration and metastasis in colorectal cancer.

OXCT1 suppresses Wnt signaling by downregulating CDK8 and reducing its interaction with β-catenin.

OXCT1 regulates CDK8 expression through histone H3 acetylation, and its reduced expression correlates with poor outcomes in CRLM.

Abstract

Colorectal cancer (CRC) poses a significant global health challenge, with liver metastasis being a major contributor to its high mortality rate. The liver, due to its strategic anatomical location, distinctive tissue architecture, and unique metabolic properties, is the primary site for CRC to metastasize. The objective of this study was to identify hub genes involved in colorectal liver metastasis (CRLM) using a combination of bioinformatics analysis and experimental methods, and to decipher their molecular mechanisms that regulate this metastatic process. By mining data from the TCGA and GEO databases, we identified that low expression of 3-ketoacid CoA transferase 1 (OXCT1) might related to the development of CRLM. Both in vitro and in vivo experiments have indicated that the downregulation of OXCT1 significantly enhanced tumor migration and metastasis, suggesting a potential tumor-suppressive role for OXCT1 in the progression of CRLM. Further bioinformatics analysis, dual-luciferase reporter assays, and Western blot identified Yin Yang 1 (YY1) as a transcription factor regulating OXCT1 in CRC. RNA sequencing suggested that OXCT1 suppressed the Wnt signaling pathway by downregulating CDK8 expression, and diminishing its interaction with β-catenin. Additionally, OXCT1 governed CDK8 expression via histone H3 acetylation. Finally, OXCT1 expression was significantly reduced in CRLM sites, which correlated with unfavorable outcomes. Our research suggested the OXCT1/Wnt signaling axis pathway as a critical regulator of CRLM. And these findings offered valuable insights, and potential therapeutic targets for CRLM.

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