Targeted methylation of cg24067911 suppresses colorectal cancer metastasis through BCL6-ATXN1-CDH1 axis

DNA methylation plays a crucial role in the progression and metastasis of colorectal cancer (CRC), yet the mechanisms underlying its effect at specific loci remain poorly understood. We previously identified cg24067911 hypomethylation as a potential biomarker associated with poor CRC prognosis. To investigate the role of cg24067911 methylation in CRC metastasis and elucidate its underlying molecular mechanisms, we utilized the CRISPR-dCas9-DNMT3a system to specifically modify the methylation status of cg24067911. Then, we performed high-throughput transposase-accessible chromatin sequencing, RNA sequencing, and chromatin immunoprecipitation analysis. We demonstrated that cg24067911 was located within an enhancer region of the ATXN1 gene, where it was bound by BCL6. Hypomethylation of cg24067911 improved the binding of BCL6 to this enhancer, leading to upregulated transcription of ATXN1. Furthermore, ATXN1 was found to act as a transcription factor that upregulates CDH2, promoting epithelial-mesenchymal transition and facilitating CRC metastasis. These findings not only reveal that cg24067911 methylation modulates CRC metastasis through a novel epigenetic mechanism involving ATXN1 and CDH2, but also highlight cg24067911 as a potential prognostic marker for CRC and suggest that targeted epigenetic therapies could be an effective strategy for treating CRC metastasis in the future.