Moon Yunwon, Chae Sehyun, Yim Sujin, Yang Eun Gyeong, Choe Jungwoo, Hyun Jiyeon, Chang Rakwoo, Hwang Daehee, Park Hyunsung
Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea.
Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Republic of Korea.
iScience. 2022 Jun 3;25(7):104517. doi: 10.1016/j.isci.2022.104517. eCollection 2022 Jul 15.
Clioquinol (CQ) is a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1α specific asparaginyl hypoxylase (FIH-1). The structural similarity of the Jumonji C (JmjC) domain between FIH-1 and JmjC domain-containing histone lysine demethylases (JmjC-KDMs) led us to investigate whether CQ could inhibit the catalytic activities of JmjC-KDMs. Herein, we showed that CQ inhibits KDM4A/C, KDM5A/B, and KDM6B and affects H3K4me3, H3K9me3, and H3K27me3 marks, respectively. An integrative analysis of the histone methylome and transcriptome data revealed that CQ-mediated JmjC-KDM inhibition altered the transcription of target genes through differential combinations of KDMs and transcription factors. Notably, functional enrichment of target genes showed that CQ and hypoxia commonly affected the response to hypoxia, VEGF signaling, and glycolysis, whereas CQ uniquely altered apoptosis/autophagy and cytoskeleton/extracellular matrix organization. Our results suggest that CQ can be used as a JmjC-KDM inhibitor, HIF-α activator, and an alternative therapeutic agent in hypoxia-based diseases.
氯碘羟喹（CQ）是一种低氧模拟物，可通过抑制低氧诱导因子-1α（HIF-1α）特异性天冬酰胺基羟化酶（FIH-1）来激活HIF-1α。FIH-1与含Jumonji C（JmjC）结构域的组蛋白赖氨酸去甲基化酶（JmjC-KDMs）之间JmjC结构域的结构相似性，促使我们研究CQ是否能抑制JmjC-KDMs的催化活性。在此，我们表明CQ可抑制KDM4A/C、KDM5A/B和KDM6B，并分别影响H3K4me3、H3K9me3和H3K27me3标记。对组蛋白甲基化组和转录组数据的综合分析表明，CQ介导的JmjC-KDM抑制通过KDMs和转录因子的不同组合改变了靶基因的转录。值得注意的是，靶基因的功能富集表明，CQ和低氧共同影响对低氧的反应、VEGF信号传导和糖酵解，而CQ独特地改变了细胞凋亡/自噬以及细胞骨架/细胞外基质组织。我们的结果表明，CQ可作为一种JmjC-KDM抑制剂、HIF-α激活剂以及基于低氧疾病的替代治疗药物。
