FBXO42 promotes hepatocellular carcinoma progression via mediating p57Kip2 ubiquitination and degradation

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BACKGROUND: Hepatocellular carcinoma (HCC), one of the most common malignancies, accounts for about 80% of all primary liver cancers. FBXO42 belongs to the F-box protein family and functions as a key component of the SCF (Skp1-Cullin-F-box) ubiquitin ligase complex, which is involved in the process of protein ubiquitination. The studies on the role of FBXO42 in different diseases are inadequate, especially in HCC. METHODS: The expression and the clinical features of FBXO42 in HCC were assessed using the HCCDB, TCGA, and ICGC databases. cBioPortal and SangerBox databases were used to analyze the genetic alterations and mutation profile of FBXO42. TIMER, TISIDB and GEPIA databases were used to examine the correlation of FBXO42 with tumor-infiltrating immune cells, tumor-associated fibroblasts and cancer stemness. CCK8 assay, clone formation assay and EDU assay were utilized to reveal the cell viability and proliferation ability. Meanwhile, transwell assay was used to assess the cellular migration. UbiBrowser and Co-IP revealed the FBXO42-interacting protein in HCC. The hTFtarget, ENCODE and CHEA databases were used to predict potential transcriptional regulators. RESULTS: Our data displayed that FBXO42 was highly expressed in HCC tissues and was associated with poor prognosis. Moreover, FBXO42 expression was correlated with immune cell infiltration and immune-related molecules, suggesting that FBXO42 may lead to a complex immune microenvironment in HCC. Meanwhile, our data revealed that the level of FBXO42 was positively associated with CAFs infiltration and cancer stemness. In addition, FBXO42 facilitated the malignant behaviors of HCC. Mechanistically, FBXO42 interacted p57Kip2, sequentially promoting p57Kip2 ubiquitination and degradation, ultimately leading to HCC progression. Finally, YY1 had been demonstrated to upregulate the expression of FBXO42 via transcriptional regulation. CONCLUSIONS: This study revealed that FBXO42 promotes the malignancy of HCC through FBXO42-mediated p57Kip2 ubiquitination and degradation. Our findings underscore the possibility of FBXO42 as a potential therapeutic target for HCC.

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