Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia

Yunwon Moon; Sehyun Chae; Sujin Yim; Eun Gyeong Yang; Jungwoo Choe; Jiyeon Hyun; Rakwoo Chang; Daehee Hwang; Hyunsung Park

doi:10.1016/j.isci.2022.104517

Clioquinol as an inhibitor of JmjC-histone demethylase exhibits common and unique histone methylome and transcriptome between clioquinol and hypoxia

iScience. 2022 Jun 3;25(7):104517. doi: 10.1016/j.isci.2022.104517. eCollection 2022 Jul 15.

Authors

Yunwon Moon¹, Sehyun Chae², Sujin Yim¹, Eun Gyeong Yang³, Jungwoo Choe^{1

4}, Jiyeon Hyun⁴, Rakwoo Chang⁴, Daehee Hwang⁵, Hyunsung Park^{1

4}

Affiliations

¹ Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea.
² Neurovascular Unit Research Group, Korea Brain Research Institute (KBRI), Daegu 41062, Republic of Korea.
³ Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
⁴ Department of Applied Chemistry, University of Seoul, Seoul 02504, Republic of Korea.
⁵ School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.

Abstract

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.

Keywords: Biochemistry; Molecular biology; Transcriptomics.