Targeting histone methyltransferase enhancer of zeste homolog-2 inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis

Abstract

Enhancer of zeste homolog-2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. Its role in renal epithelial- mesenchymal transition (EMT) remains unknown. In this study, we found that EZH2 and H3K27me3 were highly expressed in mouse kidney with unilateral ureteral obstruction and cultured mouse kidney proximal tubular (TKPT) cells undergoing EMT. Inhibition of EZH2with 3-deazaneplanocin A (3-DZNeP) attenuated renal fibrosis, which was associated with preserving E-cadherin expression and inhibiting Vimentin up-regulation in the obstructed kidney. Treatment with 3-DZNeP or transfection of EZH2 siRNA also inhibited TGF-b1-induced EMT of TKPT cells. Injury to the kidney or cultured TKPT cells resulted in up-regulation of Snail family transcriptional repressor 1 (Snail-1) and Twist family basic helix-loop-helix (BHLH) transcription factor 1 (Twist-1), which are 2 transcription factors, and down-regulation of phosphatase and tensin homolog, a protein tyrosine phosphatase associatedwithinhibition of PI3K-protein kinaseB(AKT) signaling; EZH2inhibition or silencing reversed all those responses. 3-DZNeP was also effective in suppressing epithelial arrest at the G2/M phase and dephosphorylating AKT and β-catenin in vivo and in vitro. These data indicate that EZH2 activation contributes to renal EMT and fibrosis through activation of multiple signaling pathways and suggest that EZH2 has potential as a therapeutic target for treatment of renal fibrosis.