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HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1

1
Department of Toxicology, University Medical Center, 55131 Mainz, Germany
2
Department of Medicine II, Hematology/Oncology, University Hospital, 60590 Frankfurt, Germany
3
Department of Pharmacology, University Medical Center, 55131 Mainz, Germany
4
Institute of Pharmacy, Department of Pharmaceutical/Medicinal Chemistry I, University of Regensburg, 93040 Regensburg, Germany
5
Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, 81675 Munich, Germany
*
Author to whom correspondence should be addressed.
Equal first author contribution.
Cancers 2019, 11(10), 1436; https://doi.org/10.3390/cancers11101436
Received: 16 August 2019 / Revised: 11 September 2019 / Accepted: 20 September 2019 / Published: 26 September 2019
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. View Full-Text
Keywords: AML; β-catenin; HDAC; HDACi; indomethacin; molecular marker; MYC; WT1 AML; β-catenin; HDAC; HDACi; indomethacin; molecular marker; MYC; WT1
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MDPI and ACS Style

Beyer, M.; Romanski, A.; Mustafa, A.-H.M.; Pons, M.; Büchler, I.; Vogel, A.; Pautz, A.; Sellmer, A.; Schneider, G.; Bug, G.; Krämer, O.H. HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1. Cancers 2019, 11, 1436. https://doi.org/10.3390/cancers11101436

AMA Style

Beyer M, Romanski A, Mustafa A-HM, Pons M, Büchler I, Vogel A, Pautz A, Sellmer A, Schneider G, Bug G, Krämer OH. HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1. Cancers. 2019; 11(10):1436. https://doi.org/10.3390/cancers11101436

Chicago/Turabian Style

Beyer, Mandy; Romanski, Annette; Mustafa, Al-Hassan M.; Pons, Miriam; Büchler, Iris; Vogel, Anja; Pautz, Andrea; Sellmer, Andreas; Schneider, Günter; Bug, Gesine; Krämer, Oliver H. 2019. "HDAC3 Activity is Essential for Human Leukemic Cell Growth and the Expression of β-catenin, MYC, and WT1" Cancers 11, no. 10: 1436. https://doi.org/10.3390/cancers11101436

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