Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus

Abstract

Activation of Raf reduces the repressive histone mark H3K27me3 at the INK4a locus by inducing the H3K27me3 demethylase JMJD3. During hypoxia, the catalyitc activity of JMJD3 is reduced due to the limited availability of O 2 as a substrate. In our study, we found that hypoxia prevented Raf-induced JMJD3 from demethylating H3K27me3 at the INK4a locus. Nonetheless, hypoxia did not prevent Raf signaling from inducing INK4a mRNA. Interestingly, we found that hypoxia strongly enhanced the active histone mark H3K4me3 at the INK4a locus by inhibiting the H3K4me3 demethylases JARID1A and JARID1B. Therefore, this study demonstrates that the O 2 concentration in the microenvironment differentially affects the repressive methylation on K27 and the activating methylation on K4 at the INK4a locus by inhibiting the H3K27me3 and H3K4me3 demethylases.

Histone demethylase KDM6B regulates 1,25‐dihydroxyvitamin D3‐induced senescence in glioma cells

“…KDM6B‐catalyzed H3K27me3 demethylation is vital for INK4A activation. Recent studies show that KDM6B can enhance INK4A expression (Chang et al, ; Zhao et al, ). KDM6B is recruited to INK4A promoters and activates the transcription of INK4A by eliminating repressive H3K27me3 epigenetic marks (Agger et al, ; Barradas et al, ), which causes cellular senescence.…”

“…activation. Recent studies show that KDM6B can enhance INK4A expression (Chang et al, 2016;Zhao et al, 2013). KDM6B is (Agger et al, 2009;Barradas et al, 2009), which causes cellular senescence.…”

JARID1 Histone Demethylases: Emerging Targets in Cancer

“…Accordingly, hypoxia blocked JARID1B’s repression of promoters for genes regulated by the androgen receptor in prostate cancer cells [61]. Low O 2 was similarly shown to block JARID1A’s demethylase-dependent repression of promoters [62, 63], although this isoform does not appear susceptible to HIF1α–dependent effects [60]. Regardless, increases in all the isoforms have been reported under hypoxia [64] and may primarily be an adaptive response for maintaining their normoxic functions [63].…”

“…Low O 2 was similarly shown to block JARID1A’s demethylase-dependent repression of promoters [62, 63], although this isoform does not appear susceptible to HIF1α–dependent effects [60]. Regardless, increases in all the isoforms have been reported under hypoxia [64] and may primarily be an adaptive response for maintaining their normoxic functions [63]. However, hypoxia could hypothetically also mediate a shift toward demethylase-independent gene regulatory effects that support tumor progression in a hypoxic milieu.…”

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

“…Changes of these histone marks are associated with altered expression of E-cadherin, plakoglobin, N-cadherin, and Vimentin that are involved in epithelial-mesenchymal transition [87]. In addition, the demethylase activity of JMJD proteins such as JMJD3 and JARID1A/B, is impaired under hypoxic conditions, due to limited availability of their substrate O 2 [88], which contributes to increased trimethyl K27 and K4 of histone H3, respectively [88, 89]. The global increases of dimethyl and trimethyl K9 of histone H3, trimethyl K36 of histone H3, dimethyl K79 of histone H3, acetyl K14 of histone H3, and dimethyl arginine 3 of histone H4 are also found under hypoxic conditions [87, 90].…”