TY  - JOUR
A1  - Beyer, Mandy
A1  - Romanski, Annette
A1  - Al-Hassan, M. Mustafa
A1  - Pons, Miriam
A1  - Büchler, Iris
A1  - Vogel, Anja
A1  - Pautz, Andrea
A1  - Sellmer, Andreas
A1  - Schneider, Günter
A1  - Bug, Gesine
A1  - Krämer, Oliver Holger
T1  - HDAC3 activity is essential for human leukemic cell growth and the expression of β-catenin, MYC, and WT1
T2  - Cancers
N2  - 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.
KW  - AML
KW  - β-catenin
KW  - HDAC
KW  - HDACi
KW  - indomethacin
KW  - molecular marker
KW  - MYC
KW  - WT1
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51099
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-510993
SN  - 2072-6694
N1  - 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
VL  - 11
IS  - 10, Art. 1436
SP  - 1
EP  - 20
PB  - MDPI
CY  - Basel
ER  -