@@@@Highlights •Identification of Cdh1 as an E3 ligase for SLC35F2 protein.•Cdh1 interact with and ubiquitinates SLC35F2 and decline its protein half-life.•The expression of Cdh1 and SLC35F2 shows a negative correlation in several cancers.•Depletion of Cdh1 promotes cell proliferation and SLC35F2-mediated carcinogenesis.