HDAC3 activity is essential for human leukemic cell growth and the expression of β-catenin, MYC, and WT1

  • Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors β-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of β-catenin. Indomethacin destabilizes β-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of β-catenin by WT1. In conclusion, reduced levels of β-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression.

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Author:Mandy Beyer, Annette Romanski, M. Mustafa Al-Hassan, Miriam Pons, Iris Büchler, Anja Vogel, Andrea Pautz, Andreas Sellmer, Günter Schneider, Gesine Bug, Oliver Holger Krämer
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31561534
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/09/26
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/10/14
Tag:AML; HDAC; HDACi; MYC; WT1; indomethacin; molecular marker; β-catenin
Issue:10, Art. 1436
Page Number:20
First Page:1
Last Page:20
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0