The Hypoxia-Inducible Epigenetic Regulators Jmjd1a and G9a Provide a Mechanistic Link between Angiogenesis and Tumor Growth

Abstract

dHypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as seminomas, yolk sac tumors, and embryonal carcinomas. Jmjd1a was not essential for stem cell self-renewal but played a crucial role as a tumor suppressor in opposition to the hypoxia-regulated oncogenic H3K9 methyltransferase G9a. Importantly, loss of Jmjd1a resulted in increased tumor growth, whereas loss of G9a produced smaller tumors. Pharmacological inhibition of G9a also resulted in attenuation of tumor growth, offering a novel therapeutic strategy for germ cell-derived tumors. Finally, Jmjd1a and G9a drive mutually opposing expression of the antiangiogenic factor genes Robo4, Igfbp4, Notch4, and Tfpi accompanied by changes in H3K9 methylation status. Thus, we demonstrate a novel mechanistic link whereby hypoxia-regulated epigenetic changes are instrumental for the control of tumor growth through coordinated dysregulation of antiangiogenic gene expression. Growing solid tumors develop shortages of oxygen (hypoxia) and nutrient supplies. Cancer cells induce the formation of new blood vessels from surrounding host tissues to overcome these adverse conditions. Hypoxia-inducible factors (HIFs) drive the transcriptome of cells to adapt to low-oxygen conditions (1-3). It is now increasingly evident that cancer cells adapted to hypoxia have more-malignant phenotypes (4-7). These findings raise the possibility that hypoxia effectuates long-term adaptation to low-oxygen conditions by altering the epigenetic landscape of cancer cells. However, how hypoxia, HIFs, and possibly other coregulated proteins affect the epigenetic status of oxygen-deprived cancer cells to promote malignancy remains largely unknown.To examine the impact of hypoxia on cancers, we previously examined global gene expression profiles of seven human cell lines of diverse cancer origins and found that JMJD1A (Jumonji domain-containing 1A, also known as JHDM2A and KDM3A) is one of the epigenetic factors most commonly induced by hypoxia (3). Consistent with this result, other studies have shown that JMJD1A and other Jumonji domain-containing proteins are upregulated in response to hypoxia and that HIF-1␣ is directly involved in this activation (8, 9). Jumonji domain-containing proteins have been identified as histone lysine demethylases and require Fe(II) and ␣-ketoglutarate for their catalytic activity (10). Among them, JMJD1A demethylates mono-and dimethylated histone H3 lysine 9 (H3K9) residues. JMJD1A also acts as a coactivator in cooperation with the androgen receptor (11), and it has been proposed to operate downstream of HIF-1␣ to activate target genes under hypoxic conditions (9). While Jmjd1a Ϫ/Ϫ mice are viable, males show defects in spermatogenesis leading to infertility, and both genders display an obese phenotype (12)(13)(...

G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

“…In addition, the expression levels of G9a are often up-regulated in various human cancers (27). Depletion of G9a in cancer cells inhibits cell growth, leads to chromosome instability, and markedly reduces tumor growth (28)(29)(30). Interestingly, signaling of DNA damage in senescent cells induces proteasome-dependent degradation of G9a (31) and application of a G9a inhibitor (UNC0638) in combination with a low dose of the DNA damage agents phleomycin and etoposide is shown to selectively attenuate cancer-cell proliferation (32).…”

Hypoxic Preconditioning Increases the Neuroprotective Effects of Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury

“…Taken together, our results suggest that Vegf expression of transplanted H-MSCs and/or Bdnf expression at the spinal cord lesion site promote autophagy for neuroprotective remodeling, resulting motor functional recovery. Although hypoxic preconditioning is able to improve the therapeutic potential of H-MSC, previous researches reported the epigenetic changes due to hypoxia culture [45][46][47][48]. Therefore, it is still essential to investigate the epigenetic changes in the MSCs cultured in the hypoxia condition.…”

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

“…Treatment of BIX01294 blocks expression of the HIF target gene VEGFA . Pharmacological or genetic inhibition of G9a prevents tumorigenesis in mice [40, 41]. G9a is induced by hypoxia at both transcriptional and posttranslational levels in embryonic stem cells and cancer cells and may mediate hypoxia-induced gene repression through increasing dimethyl K9 of histone H3 in cancer cells [41–43].…”