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<p>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 <i>MMR</i> 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 <i>MMR</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Quanpeng Qiu,
  • Yi Ding,
  • Jing Han,
  • Xiaolong Guo,
  • Jiaqi Zhang,
  • Yue Chen,
  • Xinzhu Xue,
  • Xiake Hu,
  • Tianyu Yu,
  • Gaixia Liu,
  • Haowei Zhang,
  • Qixin Li,
  • Xiang Li,
  • Junjun She,
  • Yinnan Chen

摘要

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.