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.

Fbxo22 在致癌作用中的重要性已得到充分证明。在这里，我们讨论了 TNBC 中 Fbxo22 的下游调控因素。进行RNA测序以鉴定差异表达基因，然后构建调控网络。TNBC 中 Fbxo22/KDM5A 的表达模式通过其与分析的预后的相关性来确定。然后，分析了Fbxo22和KDM5A之间以及KDM5A和H3K4me3之间的调节机制。经过沉默和过表达实验，探索了 Fbxo22 在体外和体内抑制肿瘤发生的意义。Fbxo22 在 TNBC 中表达较差，而 KDM5A 高表达。Fbxo22 升高、KDM5A 降低或 p16 升高的患者总生存期较长。Fbxo22 通过泛素化降低 KDM5A 的水平。KDM5A 促进组蛋白 H3K4me3 去甲基化，从而下调 p16 表达。Fbxo22 降低 KDM5A 表达以增强 p16，从而诱导 DNA 损伤并减少 TNBC 中的肿瘤发生和转移。我们的研究通过 KDM5A 泛素化和 p16 的调节验证了 FBXO22 作为 TNBC 的肿瘤抑制因子。