SETD8-mediated mono-methylation of YAP at K76 promotes K48-linked polyubiquitination and degradation to suppress colorectal cancer​​

However, the functional relevance of site-specific post-translational modifications (PTMs) in YAP, particularly methylation, remains insufficiently explored. SET-domain-containing protein 8 (SETD8), the sole monomethyltransferase for histone 4 lysine 20 (H4K20), is implicated in various cancers, yet its biological function and underlying mechanisms in CRC are elusive.

While SETD8 is primarily known for its histone methylation activity, its capacity to modify non-histone proteins, such as YAP, remains largely unexplored. This study aimed to demonstrate that SETD8 exerted a tumor-suppressive effect on CRC by inhibiting YAP protein expression. Mechanistically, SETD8 physically interacts with YAP to catalyze monomethylation at lysine 76 (K76me).