ROS‑mediated hypomethylation of PRDX5 promotes STAT3 binding and activates the Nrf2 signaling pathway in NSCLC

Abstract

Deoxyribonucleic acid (DNA) epigenetic modification has been linked to specific sequences of CpG islands and plays roles in the progression of lung cancer. In this study, it was found that peroxiredoxin-5 ( PRDX5 ) was highly expressed in non-small cell lung cancer (NSCLC) tissues; however, its specific regulatory mechanisms and functions in NSCLC remain unknown. The present study therefore explored the regulatory mechanism of PRDX5 under conditions of oxidative stress (OS) in NSCLC. The results revealed that 79 of 121 NSCLC patients exhibited demethylation in the PRDX5 promoter region, which was related to the tumor, node and metastasis (TNM) stage (P=0.027). PRDX5 messenger ribonucleic acid (mRNA) expression positively correlated with the demethylation status of the promoter region. The results of bisulfite sequencing polymerase chain reaction (BSP) revealed lower demethylation frequencies in H1299 cells treated with 0 µ M H 2 O 2 , but maximum demethylation following treatment with 100 µ M H 2 O 2 . Using chromatin immunoprecipitation (ChIP) and luciferase detection assays, the effective binding of STAT3 to the transcriptional binding sites of the PRDX5 promoter region was confirmed (2 sites confirmed: Site 1, -444 to -434 bp; and site 4, -1,417 to -1,407 bp). STAT3 knockdown significantly decreased the protein expression of PRDX5 , while the overexpression of STAT3 significantly increased the protein levels of PRDX5 . When PRDX5 was overexpressed in lung cancer cells under conditions of OS, the levels of the epithelial-mesenchymal transition (EMT) biomarkers, E-cadherin and vimentin, were significantly decreased and increased, respectively. By contrast, PRDX5 knockdown resulted in significantly increased E-cadherin and decreased vimentin protein expression levels. Ultimately, when PRDX5 -small interfering RNA (siRNA) or pcDNA3.1- PRDX5 expression vector were constructed and transfected into H1299 cells pre-treated with 100 µ M H 2 O 2 , the nuclear factor (erythroid-derived 2)-like 2 ( Nrf2 ) signaling pathway was inhibited or activated. All these results suggested that the reactive oxygen species (ROS)-mediated hypomethylation of PRDX5 enhanced STAT3 binding affinity with the promoter region, and resulted in the promotion of cell migration and invasion, as well as in the activation of the Nrf2 signaling pathway in NSCLC. The demethylation status of the PRDX5 promoter may...

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