Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells

Abstract

BackgroundThe prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The α1,6-fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery.MethodsBinding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L-fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) -inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro.ResultsThe knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3-expressing HCC cells in a p53- and FUT8-dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells.ConclusionsOur findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC.

Prognostic role of FUT8 expression in relation to p53 status in stage II and III colorectal cancer

“…In the 2 remaining cohorts, including GSE39084 and GSE35896, FUT8 mRNA seemed to be consistently highly expressed in p53 wild-type tumors compared to those with mutant p53, although it did not reach statistical significance probably due to the relatively small sample size in those cohorts. Those findings might seem consistent with our hypothesis that FUT8 expression can be regulated by p53, as the recent report has demonstrated that FUT8 is a direct transcriptional target of wild-type p53 [ 14 ].…”

“…This suggests that alterations of p53 can cause dysregulation of FUT8 mRNA levels possibly through transcriptional mechanism. As the FUT8 promotor region is likely to carry the responsive element of wild-type p53 [ 14 ], loss of wild-type p53 function due to TP53 mutations might be responsible for the altered FUT8 mRNA expression. However, this finding was not confirmed in FUT8 protein levels, in which no association was found between FUT8 expression and abnormal p53 expression by IHC.…”

“…It is worth noting that core fucosylation of alpha-fetoprotein (AFP-L3 fraction) due to the upregulation of FUT8 in HCC cells is a FDA-approved serum tumor marker for the specific diagnosis of HCC [ 12 , 13 ]. Also, a recent study has demonstrated that FUT8 can be transcriptionally activated by wild-type p53, encoded by tumor suppressor gene TP53, through p53 biding to its responsive elements within the FUT8 promotor region in HCC [ 14 ]. Since p53 alterations are found frequently (~50%) not only in HCC but also in CRC and other cancer types, the expression and function of FUT8 may be modulated by p53 in human cancers.…”

α,1,6-Fucosyltransferase (FUT8) regulates cancer-promoting capacities of cancer-associated fibroblasts (CAFs) through the modification of EGFR core fucosylation in non-small cell lung cancer

“…In the current study, the silencing of FUT8 in CAFs and the upregulation of It was showed by the GSEA that the low expression of FUT8/CF led to inhibition of both extrinsic and intrinsic apoptosis pathways. There has been a debate about the effect of FUT8/CF on cell apoptosis in different types of cell and tissue as some researchers reported promotion [66][67][68] , and one reported inhibition [69] . However, whether it was the reason of the inhibited capacity of FUT8 low-expressing CAFs remains unknown.…”

Application of Mono‐ and Disaccharides in Drug Targeting and Efficacy

“…l ‐Fucose‐specific lectins are powerful tools used in the laboratory diagnosis of major human malignancies including leukemia, SW480 colon cancer, and stomach and breast carcinomas among others . Fucosyltransferases (FucTs) are responsible for accelerating malignant transformation by means of fucosylation of sialylated precursors; that is, the formation and development of cancer cells require crucial fucoses, offering the basis for l ‐fucose‐mediated drug delivery to target hepatocellular carcinoma (HCC) cells as a therapeutic strategy . l ‐Fucose‐anchored methotrexate‐loaded solid lipid nanoparticles (SLNs) have been designed to target breast cancer, and it was found that relative to free drug, in vivo maximum bioavailability and tumor targeting efficiency markedly increased, together with the minimum secondary drug distribution in various organs with the formulated and anchored nanocarrier .…”