FBXO28是F-box蛋白家族的成员，这些蛋白是SCF（SKP1、CULLIN1、F-box蛋白）泛素连接酶复合物的底物受体。尽管其在癌症中的作用有所暗示，但FBXO28在上皮间质转变（EMT）过程和肿瘤转移中的功能仍然被大部分未知。我们在这里报告FBXO28在体内外对人肝细胞癌（HCC）的迁移、侵袭和转移过程中是关键的负调控蛋白。FBXO28的表达在人上皮癌细胞系相对于间质对应物有上调。机制上，通过直接与SNAI2结合，FBXO28作为一个E3泛素连接酶在泛素蛋白酶体系统中定位底物以进行降解。重要的是，我们确立了PKA在FBXO28介导的SNAI2降解中的合作功能。在临床HCC标本中，FBXO28蛋白水平与PKAα和SNAI2水平呈正和负相关。低FBXO28或PRKACA表达与HCC患者的预后不佳相关。总之，这些发现阐明了FBXO28作为肿瘤中EMT和转移的关键抑制因子的新功能，并为其作为人类侵袭性HCC的新预后标志物和/或治疗靶点的候选理论提供了机制基础。©2023年。作者。

FBXO28 is a member of F-box proteins that are the substrate receptors of SCF (SKP1, CULLIN1, F-box protein) ubiquitin ligase complexes. Despite the implications of its role in cancer, the function of FBXO28 in epithelial-mesenchymal transition (EMT) process and metastasis for cancer remains largely unknown. Here, we report that FBXO28 is a critical negative regulator of migration, invasion and metastasis in human hepatocellular carcinoma (HCC) in vitro and in vivo. FBXO28 expression is upregulated in human epithelial cancer cell lines relative to mesenchymal counterparts. Mechanistically, by directly binding to SNAI2, FBXO28 functions as an E3 ubiquitin ligase that targets the substrate for degradation via ubiquitin proteasome system. Importantly, we establish a cooperative function for PKA in FBXO28-mediated SNAI2 degradation. In clinical HCC specimens, FBXO28 protein levels positively whereas negatively correlate with PKAα and SNAI2 levels, respectively. Low FBXO28 or PRKACA expression is associated with poor prognosis of HCC patients. Together, these findings elucidate the novel function of FBXO28 as a critical inhibitor of EMT and metastasis in cancer and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human aggressive HCC.© 2023. The Author(s).