Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation.

ABSTRACT: The importance of Fbxo22 in carcinogenesis has been highly documented. Here, we discussed downstream regulatory factors of Fbxo22 in TNBC. RNA-sequencing was conducted for identifying differentially expressed genes, followed by construction of a regulatory network. Expression patterns of Fbxo22/KDM5A in TNBC were determined by their correlation with the prognosis analyzed. Then, regulation mechanisms between Fbxo22 and KDM5A as well as between KDM5A and H3K4me3 were assayed. After silencing and overexpression experiments, the significance of Fbxo22 in repressing tumorigenesis in vitro and in vivo was explored. Fbxo22 was poorly expressed, while KDM5A was highly expressed in TNBC. Patients with elevated Fbxo22, decreased KDM5A, or higher p16 had long overall survival. Fbxo22 reduced the levels of KDM5A by ubiquitination. KDM5A promoted histone H3K4me3 demethylation to downregulate p16 expression. Fbxo22 reduced KDM5A expression to enhance p16, thus inducing DNA damage as well as reducing tumorigenesis and metastasis in TNBC. Our study validated FBXO22 as a tumor suppressor in TNBC through ubiquitination of KDM5A and regulation of p16.

SUBMITTER: Li S 

PROVIDER: S-EPMC10425479 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature