Open AccessBelinostat, a potent HDAC i, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling
Author(s) -
Valiuliene Giedre,
Stirblyte Ieva,
Cicenaite Dovile,
Kaupinis Algirdas,
Valius Mindaugas,
Navakauskiene Ruta
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12550
Subject(s) - histone , chromatin , histone h4 , epigenetics , cancer research , biology , acetylation , histone acetyltransferases , pcaf , cell growth , chromatin immunoprecipitation , chromatin remodeling , microbiology and biotechnology , chemistry , gene expression , promoter , gene , genetics
Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases ( HDAC is) are widely accepted as an attractive strategy for acute promyelocytic leukaemia ( APL ) treatment. Belinostat (Bel, PXD 101), a hydroxamate‐type HDAC i, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL , is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid ( RA ) on human promyelocytic leukaemia NB 4 and HL ‐60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers ( HDAC 1, HDAC 2, PCAF ) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up‐regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB 4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro‐apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDAC i Bel action on APL cells.