Nevertheless, the impact of HIPK1 on PAGE4 function is largely cell type-specific, namely enhancing PAGE4 protection on ROS in LNCaP cells that express functional AR but attenuating PAGE4 function in DU145 cells, in which AR is silenced. male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear. Methods Western blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues. Results In this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2. Conclusion Our findings indicate that AC-42 PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications. Electronic supplementary material The online version of this article (10.1186/s13046-019-1032-3) contains supplementary material, which is available to authorized C1qtnf5 users. However, when we checked the expression of several tumor less aggressiveness-related genes, such as ACTA2 , FBLN1 , AC-42 F2R , we found that the expressions of these genes were increased upon overexpression of PAGE4. In addition, RNA sequencing data confirmed that a panel of metastasis-related genes were attenuated in PAGE4 overexpressing cells. In support, higher expression of PAGE4 predicted a better DFS of PCa in TCGA dataset, adhering to its inhibitory role of tumor aggressiveness. This is consistent with our previous finding that PAGE4 mRNA level was among markers correlated with a good prognosis of PCa . Additionally, the previous finding that PAGE4 protein was detected more often in localized PCa than metastatic cancer highlights again the reverse correlation between PAGE4 expression and cancer aggressive phenotype . Intriguingly, AC-42 a recent elegant study links PAGE4 to the dynamic androgen-dependence and speculates that PAGE4 interacts with particular kinase suppresses AR hyperactivity and therefore makes cells sensitive to androgen deprivation (ADT) treatment , which may certainly lead to longer DFS. However, given that many metastatic PCa that are lack of PAGE4 expression are sensitive to ADT initially, it still could not be excluded that PAGE4 impacts cancer aggressiveness beyond ADT sensitivity. Thus, it is possible that PAGE4 blocks the development of aggressive PCa through attenuating the cell damage caused by oxidative stress which exists in the tumor microenvironment. To this rate, PAGE4 expression in PCa cells is potentially to be a predictive biomarker for good cancer prognosis, although it might promote tumor growth in primary site. In consistent with our previous finding that PAGE4 is a stress-response protein , we here AC-42 confirmed that PAGE4 expression was remarkably induced by ROS stimuli not only in cell models but also in xenografted tumor tissues. Notably, both endogenous PAGE4 expression and exogenously transfected PAGE4 construct can be induced by H2O2. This phenomenon was also noticed in our previous study, in which exogenously expressed PAGE4 was increased after treating cells with TNF-.