Lysines 207 and 325 methylation of WDR5 catalyzed by SETD6 promotes breast cancer cell proliferation and migration.

Accumulating evidence has revealed that the methylation of lysines on nonhistones by histone lysine methyltransferases (HMTs) is crucial for regulating tumo-rigenesis and metastasis. However, whether the methy-lation of lysines on HMT complex components occurs and has functions in cancer progression is less well understood. WD repeat domain 5 (WDR5) is a core component of an HMT complex named mixed lineage leukemia (MLL)/Suppressor of Variegation, Enhancer of Zeste, and Trithorax 1 (SET1). In the present study, it was reported that lysines 207 and 325 (K207 and K325, respectively) of WDR5 were monomethylated by SET‑domain‑containing protein methyltransferase 6. Disrupting the methylation of K207/K325 via a K207R/K325R double‑site mutation attenuated the WDR5 promotion of breast cancer cell proliferation and migration. Methylation of K207/K325 on WDR5 partially contributed to maintaining global histone tri‑methylation of lysine 4 on histone H3 levels, but did not affect MLL/SET1 complex assembly. These results further understanding of a potential post‑translational modification of WDR5, and imply that the methylation of lysines on HMT complex components is crucial for regulating human carcinogenesis.