Sasaki Yuji, Higashijima Yoshiki, Suehiro Jun-Ichi, Sugasawa Takehito, Oguri-Nakamura Eri, Fukuhara Shigetomo, Nagai Nao, Hirakawa Yosuke, Wada Youichiro, Nangaku Masaomi, Kanki Yasuharu
Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo 113-0033, Japan; Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Biochem Biophys Res Commun. 2022 May 21;605:16-23. doi: 10.1016/j.bbrc.2022.03.054. Epub 2022 Mar 12.
Vascular endothelial growth factor (VEGF) signaling plays a central role in vascular development and maintenance of vascular homeostasis. In endothelial cells (ECs), VEGF activates the gene expression of angiogenic transcription factors (TFs), followed by induction of downstream angiogenic responsive genes. Recent findings support that histone modification dynamics contribute to the transcriptional control of genes that are important for EC functions. Lysine demethylase 2B (KDM2B) demethylates histone H3K4me3 and H3K36me2/3 and mediates the monoubiquitination of histone H2AK119. KDM2B functions as a transcriptional repressor in somatic cell reprogramming and tumor development. However, the role of KDM2B in VEGF signaling remains to be elucidated. Here, we show that KDM2B knockdown enhances VEGF-induced angiogenesis in cultured human ECs via increased migration and proliferation. In contrast, ectopic expression of KDM2B inhibits angiogenesis. The function of KDM2B may depend on its catalytic Jumonji C domain. Genome-wide analysis further reveals that KDM2B selectively controls the transcription of VEGF-induced angiogenic TFs that are associated with increased H3K4me3/H3K36me3 and decreased H2AK119ub. These findings suggest an essential role of KDM2B in VEGF signaling in ECs. As dysregulation of VEGF signaling in ECs is involved in various diseases, including cancer, KDM2B may be a potential therapeutic target in VEGF-mediated vasculopathic diseases.
血管内皮生长因子（VEGF）信号传导在血管发育和维持血管稳态中起着核心作用。在内皮细胞（ECs）中，VEGF激活血管生成转录因子（TFs）的基因表达，随后诱导下游血管生成反应性基因。最近的研究结果支持组蛋白修饰动态变化有助于对EC功能重要的基因的转录控制。赖氨酸去甲基化酶2B（KDM2B）使组蛋白H3K4me3和H3K36me2/3去甲基化，并介导组蛋白H2AK119的单泛素化。KDM2B在体细胞重编程和肿瘤发展中作为转录抑制因子发挥作用。然而，KDM2B在VEGF信号传导中的作用仍有待阐明。在这里，我们表明，敲低KDM2B通过增加迁移和增殖增强了培养的人ECs中VEGF诱导的血管生成。相反，KDM2B的异位表达抑制血管生成。KDM2B的功能可能取决于其催化性Jumonji C结构域。全基因组分析进一步揭示，KDM2B选择性地控制与H3K4me3/H3K36me3增加和H2AK119ub减少相关的VEGF诱导的血管生成TFs的转录。这些发现表明KDM2B在ECs的VEGF信号传导中起着重要作用。由于ECs中VEGF信号传导的失调涉及包括癌症在内的各种疾病，KDM2B可能是VEGF介导的血管病变疾病的潜在治疗靶点。
