FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter

Abstract Background Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. family protein lays pivotal role in metabolism. ROS involved tumor progression associated with expression lots transcription factors. We next explored mechanism underlying FOXC1 modulating metabolism hemostasis HCC. Methods used amino acids arrays to verify which FOXC1-induced The kits were detect levels cells over-expression or down-expression FOXC1. After identified downstream target genes candidate pathway regulated by during vitro vivo, we western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis luciferase reporter assays explore relationship genes. Moreover, correlation between recurrence overall survival analyzed two independent human cohorts. Results Here, reported that could inhibit cysteine increase reactive oxygen species (ROS) regulating metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression CTH significantly suppressed proliferation, metastasis, while reduction cell metastasis caused inhibition be reversed knockdown CTH. Meanwhile, upregulated de novo DNA methylase 3B (DNMT3B) induce hypermethylation promoter, resulted low cells. induced N-acetylcysteine (NAC) an antioxidant inhibited migration, abilities mediated overexpression, whereas high L-Buthionine-sulfoximine (BSO) rescued suppression results knockdown. Our study demonstrated overexpression was dependent on extracellular kinases 1 2 (ERK1/2)- phospho-ETS Transcription Factor (p-ELK1) pathway. In tissues, positively correlated oxidative damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), p-ELK1 DNMT3B expression, but negatively expression. patients positive co-expression 8-OHdG/FOXC1 p-ELK1/FOXC1 FOXC1/DNMT3B had worst prognosis, who negative exhibited prognosis. Conclusion word, clarify feedback loop ROS-FOXC1-cysteine metabolism-ROS promoting liver cancer proliferation this may provide prospective clinical treatment approach