Epigenetically inhibiting CYP3A5 modulates the migration and invasion of esophageal squamous cell carcinoma via ZEB2

Background: Aberrant suppression of cytochrome P450 3A5 (CYP3A5) is frequently observed in human esophageal squamous cell carcinoma (ESCC); however, its role and the epigenetic mechanism mediating transcriptional repression of CYP3A5 in ESCC remain poorly understood. Results: : Herein, we examined the expression and prognostic role of CYP3A5 in tumor tissues obtained from patients with ESCC. CYP3A5 silencing correlated with poor survival in ESCC. Using the histone deacetylase (HDAC) inhibitor trichostatin A (TSA), RNA interference, reporter gene assays, and chromatin immunoprecipitation, HDAC4 was found to be the key enzyme responsible for the absence of H3K18/K27Ac, mediated via P300/CBP at the CYP3A5 promoter. Finally, using CYP3A5 knockdown, re-expression, and xenograft experiments, we demonstrated that CYP3A5 downregulation, resulting in ZEB2 activation, promoted ESCC invasion and migration. Conclusions: : our findings indicate that CYP3A5 activation reverses ZEB2-induced epithelial-mesenchymal transition (EMT) and inhibits migration and invasion of ESCC cells.