Abstract
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.
Highlights
It is estimated that there will be 437,033 new cases of leukemia and 309,006 deaths associated worldwide in 2018 [1]
After 24 h, 10 nM LBH589 induced a three-fold increase in annexin-V-FITC-positive MV4-11 cells, which corresponds to 16% apoptotic cells. 30 nM LBH589 caused a four-fold increase of apoptosis in MV4-11 cells and a six-fold increase of apoptotic cells in HEL cells, which corresponds to 34% and 67% dead cells (Figure 1A; see Supplementary Figure S1 for exemplary dot plots)
Discussion levelsiswere not for decreased by LBH589.cells [3,4,5,6,7,8,9], to the of an additional band that was revealed by the β-catenin a enin relevant growth and survival weadvent tested whether
Summary
It is estimated that there will be 437,033 new cases of leukemia and 309,006 deaths associated worldwide in 2018 [1]. Predictions state that more than 21,450 people will be diagnosed with acute myeloid leukemia (AML) and nearly 10,920 people will die from it alone in the USA in 2019 [2] This warrants the search for new therapeutic strategies. Cancers 2019, 11, 1436 as an actionable drug target in AML, because the expression and activity of β-catenin is linked to disease initiation, unfavorable karyotypes, and poor prognosis. Cells from such patients show enhanced self-renewal capacity, which suggests that β-catenin contributes to a stemness phenotype [3,4,5,6,7,8,9].
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