Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2α

Abstract

Lysine (K)-specific demethylase 6B (KDM6B) is a histone H3K27 demethylase, which specifically catalyzes the demethylation of H3 lysine-27 tri/dimethylation (H3K27me3/2). KDM6B can activate gene transcription by promoting transcriptional elongation which is associated with RNA polymerase II and related elongation factors. So KDM6B is important for the regulation of gene expression. Previous studies have indicated that several histone demethylases such as KDM3A, KDM4B, and KDM4C are regulated by hypoxia-inducible factor (HIF). But, the effect of hypoxia on KDM6B is not fully understood. In this study, we found that the expression levels of KDM6B mRNA and protein are modestly up-regulated under hypoxia (1% O 2 ) or mimic hypoxia (desferrioxamine mesylate or CoCl 2 treatment) (P < 0.05). The result of RNAi shows that the up-regulation of KDM6B is dependent on HIF-2α, but not on HIF-1α. The result of chromatin immunoprecipitation assay indicates that there is a hypoxia response element in KDM6B promoter (−4041 to −4037). The result of Co-IP assay indicates that KDM6B can form complex with HIF-2α or HIF-1α. The knockdown experiment implies that KDM6B is a potential regulator for HIF-2α target genes. These data demonstrate that KDM6B is a new hypoxia response gene regulated by HIF-2α. Our results also show that KDM6B is a potential coactivator of HIF-α, which is important for the activation of hypoxia response genes.

Ascorbic acid induces global epigenetic reprogramming to promote meiotic maturation and developmental competence of porcine oocytes

“…First, ascorbic acid could directly induce changes of the expression or activity of JmjC-KDMs 44 . Second, since some JmjC-KDMs, including KDM5b, are known to be direct targets of HIF 41 , 45 , 46 , ascorbic acid could indirectly affect JmjC-KDMs through decreasing HIF level. Third, a significant decrease of ROS level after ascorbic acid treatment suggests that suppressing oxidative stress may be effective in inducing changes of global histone methylation.…”

The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance

“…Moreover, the KDM4 subfamily, particularly KDM4C/JMJD2C, which target methylated H3K9 and H3K36 histone marks, contributes to cancer initiation and development, and is associated with hypoxic status in breast cancer [74,75], whereas, in renal cell carcinoma cell lines, KDM3A, KDM4B and KDM5B were shown to be regulated by HIF family. Also, KDM6B/JMJD3, which demethylate H3K27me3, was previously demonstrated to play a critical role in the hypoxic signaling pathway, in the human liver and kidney cell lines [76,77]. The involvement of these main JmjC-KDMs highlight the importance of HIF-1α-dependent epigenetic regulation in hypoxia, leading to several molecular changes, like cell cycle arrest and DNA repair, which contribute to cancer progression.…”

Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation

“…There is still some debate about the carcinogenic and antitumor effects of JMJD3, because JMJD3 is overexpressed in some tumors but is lower in other tumors [ 37 , 38 ]. In mechanism, JMJD3 not only functions as tumor-suppressor by inducing cell senescence [ 33 , 34 ], but also promotes carcinogenesis via participating in hypoxia signaling pathway [ 39 ]. We propose a hypothesis for the converse result (Figure 6 ).…”