KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer (PCa). KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to PCa tumorigenesis remains unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and PCa progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of PCa in Pten-null mice, while Kdm5b loss alone caused no morphological abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduc... More
KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer (PCa). KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to PCa tumorigenesis remains unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and PCa progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of PCa in Pten-null mice, while Kdm5b loss alone caused no morphological abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared to that of Pten mice. Pathological analysis revealed Pten/Kdm5b mice displayed mild morphological changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high grade-prostatic intraepithelial neoplasia (HG-PIN) and PCa. Mechanistically, KDM5B governed phosphatidylinositol 3-kinase (PI3K)/AKT signaling in PCa in vitro and in vivo. KDM5B directly bound the PIK3CA promoter and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human PCa cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against PCa.
