The oxidative modification of transcription factor FOXM1 by Peroxiredoxin1 facilitates DNA damage repair and cancer...

The oxidative modification of proteins induced by hydrogen peroxide (H₂O₂) results in the formation of disulfide bond between two cysteines and affects protein conformation and biological function. Transcription factor FOXM1 participates in the development and progression of cancers and its levels are upregulated by the oxidative stress of H₂O₂-treated condition. In this study, we found that Peroxiredoxin-1 (PRDX1), one of the most H₂O₂-reactive antioxidant enzymes, interacted with FOXM1 and led to its oxidation under H₂O₂ stimulation through generating an intermolecular disulfide bond with FOXM1 C539, which was subsequently transferred to form an intramolecular disulfide bond between C167 and C175 in the oxidized FOXM1. The PRDX1-mediated oxidative modification enhanced the protein stability and transcriptional activity of FOXM1, which stimulated the transcription of FOXM1 target gene X-ray cross-complementing protein 1 (XRCC1) and improved the repair of H₂O₂-induced DNA damage in cancer cells. The disruption of PRDX1-mediated FOXM1 oxidation impaired the colony formation ability of cancer cells in vitro and the growth and DNA damage repair ability of cancer cells in vivo. The analysis of The Cancer Genome Atlas (TCGA) breast cancer patient data confirmed that PRDX1 and FOXM1 together facilitated clinical cancer progression. Overall, we established an H₂O₂-PRDX1-FOXM1 oxidation pathway that likely contribute to the development and progression of cancers.