2. Academic Validation
  3. K542 acetylation promotes YTHDF2 binding to m6A-modified mRNAs and fosters colorectal cancer progression

K542 acetylation promotes YTHDF2 binding to m6A-modified mRNAs and fosters colorectal cancer progression

  • Exp Cell Res. 2025 Jul 15;450(2):114667. doi: 10.1016/j.yexcr.2025.114667.
Bo Wen 1,  Shiwei Feng 2,  Lin Bao 3,  Sheng Li 1,  Yanping Yang 4,  Shiyou Long 5,  Jian Xiao 5,  Shujuan Li 6,  Yujie Hou 7,  Sisi Liu 8
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Central Hospital of Shaoyang, Shaoyang, Hunan, China.
  • 2 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangdong, China.
  • 4 Department of Pathology, The Central Hospital of Shaoyang, Shaoyang, Hunan, 422000, China.
  • 5 Department of Gastrointestinal Surgery, The Affiliated Shaoyang Hospital, Hengyang Medical School, University of South China, Shaoyang, Hunan, China.
  • 6 Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 7 Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: houyj3@mail.sysu.edu.cn.
  • 8 Department of Pathology, The Central Hospital of Shaoyang, Shaoyang, Hunan, 422000, China. Electronic address: lsstriumph@163.com.
PMID: 40623493 DOI: 10.1016/j.yexcr.2025.114667
Abstract

N6-methyladenosine (m6A) modification serves as a crucial regulator of diverse biological processes and disease progression. A central player in m6A regulation is YT521-B homology domain family member 2 (YTHDF2), a well-characterized m6A-binding protein primarily involved in mRNA stabilization. This study identifies lysine 542 (K542) as a critical acetylation site on YTHDF2, regulated by p300 as the acetyltransferase and SIRT2 as the deacetylase. Notably, while K542 acetylation has minimal effects on YTHDF2's protein stability or subcellular localization, it significantly enhances the protein's binding affinity for m6A-modified mRNAs. This enhanced binding affinity has profound biological implications, as K542 acetylation promotes malignant phenotypes in colorectal Cancer (CRC) cells in vitro and in vivo. Supporting its clinical relevance, analysis of CRC tissues reveals elevated levels of YTHDF2 acetylation in primary tumors, strongly associating this modification with CRC pathology. Collectively, these findings highlight K542 acetylation as a key enhancer of YTHDF2's m6A recognition and a critical driver of its oncogenic activity.

Keywords

Acetylation; Colorectal cancer; YTHDF2; m6A.

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