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

Steven Holshouser, Rebecca Cafiero, Mayra Robinson, Joy Kirkpatrick, Robert A. Casero, Hyacinth I. Hyacinth, Patrick M. Woster

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)14750-14758
Number of pages9
JournalACS Omega
Volume5
Issue number24
DOIs
StatePublished - Jun 23 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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    Holshouser, S., Cafiero, R., Robinson, M., Kirkpatrick, J., Casero, R. A., Hyacinth, H. I., & Woster, P. M. (2020). Epigenetic Reexpression of Hemoglobin F Using Reversible LSD1 Inhibitors: Potential Therapies for Sickle Cell Disease. ACS Omega, 5(24), 14750-14758. https://doi.org/10.1021/acsomega.0c01585