Epigenetic Reexpression of Hemoglobin F Using Reversible LSD1 Inhibitors: Potential Therapies for Sickle Cell Disease

• Type of Material: Article
• Authors: Steven Holshouser, Medical University of South Carolina; Rebecca Cafiero, Medical University of South Carolina; Mayra Robinson, Medical University of South Carolina; Joy Kirkpatrick, Medical University of South Carolina; Robert A. Casero, Jr., Johns Hopkins; Hyacinth Hyacinth, Emory University; Patrick M. Woster, Medical University of South Carolina
• Language: English
• Date: 2020-06-23
• Publisher: American Chemical Society: Open Access Titles
• Publication Version: Final Published Version
• Copyright Statement: © 2020 American Chemical Society.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/acsomega.0c01585
• Title of Journal or Parent Work: ACS Omega
• ISSN: 2470-1343
• Volume: 5
• Issue: 24
• Start Page: 14750
• End Page: 14758
• Grant/Funding Information: The research described in this manuscript was supported by a generous grant from the Doris Duke Charitable Foundation (2017091, to P.M.W.).; Compounds 4–8 were initially produced under a separate project funded by the National Institutes of Health (1 R01 CA204345, to R.A.C. and P.M.W.), but no funds from that award were used to support the studies outlined in this manuscript.
• Keywords: EXPRESSION; DEMETHYLASE 1; Physical Sciences; CANCER; RN-1; HISTONE; ORPHAN NUCLEAR RECEPTORS; Chemistry; HYDROXYUREA; Science & Technology; TR2; CYCLIC PEPTIDE INHIBITORS; Chemistry, Multidisciplinary; FETAL GLOBIN GENE
• Research Categories: Health Sciences, Oncology; Chemistry, General; Biology, Neuroscience

Abstract

Sickle cell disease (SCD) is caused by a single nucleotide polymorphism on chromosome 11 in the β-globin gene. The resulting mutant hemoglobin S (HbS) is a poor oxygen transporter and causes a variety of vascular symptoms and organ failures. At birth, the DRED epigenetic complex forms and silences the γ-globin gene, and fetal hemoglobin (HbF, 2 α-, and 2 γ-subunits) is replaced by adult HbA (α2β2) or HbS (α2βs2) in SCD patients. HbF is a potent inhibitor of HbS polymerization, thus alleviating the symptoms of SCD. The current therapy, hydroxyurea (HU), increases γ-globin and the HbF content in sickle cells but is highly underutilized due to concern for adverse effects and other complications. The DRED complex contains the epigenetic eraser lysine-specific demethylase 1 (LSD1), which appears to serve as a scaffolding protein. Our recently discovered 1,2,4-triazole derivatives and cyclic peptide LSD1 inhibitors promote the upregulation of γ-globin production in vitro without significant toxicity. Herein, we demonstrate that these LSD1 inhibitors can be used to disrupt the DRED complex and increase the cellular HbF content in vitro and in vivo. This approach could lead to an innovative and effective treatment for SCD.