| Title |
Belinostat, a potent HDACi, exerts antileukemic effect in human acute promyelocytic leukemia cells via chromatin remodelling / |
| Authors |
Valiulienė, Giedrė ; Stirblytė, Ieva ; Cicėnaitė, Dovilė ; Kaupinis, Algirdas ; Valius, Mindaugas ; Navakauskienė, Rūta |
| DOI |
10.1111/jcmm.12550 |
| Full Text |
|
| Is Part of |
Journal of cellular and molecular medicine.. Oxford : Wiley-Blackwell Publishing Ltd.. 2015, vol. 19, no. 7, p. 1742-1755.. ISSN 1582-1838. eISSN 1582-4934 |
| Keywords [eng] |
APL ; HDACi ; Belinostat ; epigenetics ; granulocytic differentiation |
| Abstract [eng] |
Epigenetic changes play a significant role in leukemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumors and hematological 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 leukemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dose used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA upregulates 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. MS analysis revealed that in control NB4 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 defense against oxidative stress and tumor suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells. |
| Published |
Oxford : Wiley-Blackwell Publishing Ltd |
| Type |
Journal article |
| Language |
English |
| Publication date |
2015 |
| CC license |
|
