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

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.