Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 17; pp. 4626 - 4638
• Main Authors: Yang, Jun, Milasta, Sandra, Hu, Dongli, AlTahan, Alaa M, Interiano, Rodrigo B, Zhou, Junfang, Davidson, Jesse, Low, Jonathan, Lin, Wenwei, Bao, Ju, Goh, Pollyanna, Nathwani, Amit C, Wang, Ruoning, Wang, Yingdi, Ong, Su Sien, Boyd, Vincent A, Young, Brandon, Das, Sourav, Shelat, Anang, Wu, Yinan, Li, Zhenmei, Zheng, Jie J, Mishra, Ashutosh, Cheng, Yong, Qu, Chunxu, Peng, Junmin, Green, Douglas R, White, Stephen, Guy, R Kiplin, Chen, Taosheng, Davidoff, Andrew M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.09.2017
• Subjects: Animals; Antifungal Agents - pharmacology; Cancer; Cancer therapies; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Epigenesis, Genetic; Epigenetics; Fungicides; Gene Expression Regulation, Enzymologic - drug effects; Histone Demethylases - antagonists & inhibitors; Histones - metabolism; Humans; Kinases; Lysine; Mice; Mice, SCID; Mitochondria; Myc protein; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - enzymology; Neuroblastoma - pathology; Neuroblastoma cells; Oxidative phosphorylation; Oxidative Phosphorylation - drug effects; Phosphorylation; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyridones - pharmacology; RNA, Small Interfering - genetics; Transcription factors; Transcription, Genetic - drug effects; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-0826

Histone lysine demethylases facilitate the activity of oncogenic transcription factors, including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells, where MYC is often overexpressed. We also identified the approved small-molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases, including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC-targeting approach for cancer therapy. .