Hypermethylation of Mig-6 gene promoter region inactivates its function, leading to EGFR/ERK signaling hyperphosphorylation, and is involved in arsenite-induced hepatic stellate cells activation and extracellular matrix deposition

Abstract

Arsenic is a widespread naturally contaminant. Previous studies have highlighted the issue of liver fibrosis induced by arsenic exposure, while the exact mechanisms are not yet fully understood. Recent studies suggest that Mig-6/EGFR/ERK signaling appear to play important roles in fibrosis caused by various factors. In this study, we focused on the epigenetic modification combined with the signaling dysregulation to validate the role of Mig-6 in regulating EGFR/ERK signaling in arsenite-induced human hepatic stellate cells (HSCs) activation. Our results revealed that arsenite exposure induced HSCs activation and extracellular matrix (ECM) deposition. The EGFR/ERK signaling was significantly hyperphosphorylated in arsenite-exposed HSCs, and Mig-6 inactivation was involved in arsenite induced hyperphosphorylation of EGFR and activation of HSCs. Additionally, we further illustrated that hypermethylation of Mig-6 gene promoter region was responsible for the downregulation of Mig-6 induced by arsenite exposure. Moreover, 5-Aza-dC (a DNA methyltransferase inhibitor) can efficiently rescue hypermethylation of Mig-6 gene, decrease the hyperphosphorylation of EGFR/ERK signaling, then reverse arsenite induced HSCs activation. Taken together, the present study strongly suggests that inactivating of Mig-6 function by hypermethylation of its promoter region leading to hyperphosphorylation of EGFR/ERK signaling, and is involved in arsenite-induced HSCs activation and ECM deposition.

Keywords: Arsenite; DNA methylation; EGFR/ERK signaling; Liver fibrosis; Mitogen-inducible gene-6.