EZH2 deficiency suppresses colorectal cancer progression by inhibiting the mismatch repair pathway and consequently reducing extrachromosomal circular DNA formation.

The malignant transition of colorectal cancer (CRC) is caused by the combined action of epigenetic dysregulation and genomic instability. It is well known that EZH2-directed H3K27me3 modification is one of the main contributors to tumorigenesis; however, how it affects the DNA mismatch repair (MMR) system and the genesis of extrachromosomal circular DNA (eccDNA) remains unknown. Here, we demonstrate that EZH2 epigenetically represses critical MMR genes, which results in genomic instability and abnormal eccDNA accumulation, ultimately accelerating CRC progression. On the molecular level, the H3K27me3 mark catalyzed by EZH2 is the main cause of the downregulation of MMR genes, which affects the stability of the genome and leads to an increase in eccDNA that makes the tumor more aggressive. Our study reveals an unprecedented role of EZH2 in controlling chromosomal instability and eccDNA production through the MMR pathway and offers a conceptual framework for the development of CRC-targeted epigenetic therapies.