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

Abstract

Hypoxia 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 anti-angiogenic factors Robo4, Igfbp4, Notch4 and Tfpi accompanied by changes in H3K9 methylation status. Thus, we demonstrate a novel mechanistic link where hypoxia-regulated epigenetic changes are instrumental for the control of tumor growth through coordinated dysregulation of anti-angiogenic gene expression.