Abstract
We previously identified novel thiazole derivatives able to reduce histone acetylation and histone acetyltransferase (HAT) activity in yeast. Among these compounds, 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) has been selected and used throughout this study. The effect of CPTH6 on histone acetylation, cell viability and differentiation, cell-cycle distribution, and apoptosis in a panel of acute myeloid leukemia and solid tumor cell lines has been evaluated. Here, we showed that CPTH6 leads to an inhibition of Gcn5 and pCAF HAT activity. Moreover, it inhibits H3/H4 histones and α-tubulin acetylation of a panel of leukemia cell lines. Concentration- and time-dependent inhibition of cell viability, paralleled by accumulation of cells in the G(0)/G(1) phase and depletion from the S/G(2)M phases, was observed. The role of mitochondrial pathway on CPTH6-induced apoptosis was shown, being a decrease of mitochondrial membrane potential and the release of cytochrome c, from mitochondria to cytosol, induced by CPTH6. Also the involvement of Bcl-2 and Bcl-xL on CPTH6-induced apoptosis was found after overexpression of the two proteins in leukemia cells. Solid tumor cell lines from several origins were shown to be differently sensitive to CPTH6 treatment in terms of cell viability, and a correlation between the inhibitory efficacy on H3/H4 histones acetylation and cytotoxicity was found. Differentiating effect on leukemia and neuroblastoma cell lines was also induced by CPTH6. These results make CPTH6 a suitable tool for discovery of molecular targets of HAT and, potentially, for the development of new anticancer therapies, which warrants further investigations.
Highlights
Epigenetic changes, including histone modifications, often occur in cancer [1]
To identify the specific target(s) of CPTH6, a thiazole derivative (Supplementary Fig. S1A) previously shown to inhibit histone acetylation in yeast [24], we analyzed the effect of the compound on in vitro Histone acetyltransferases (HAT) activity of human recombinant p300, CBP, pCAF, and Gcn5 enzymes
We found that the increase of acetyl-CoA concentration reverted the inhibitory effect of CPTH6 on Gcn5 HAT activity (Supplementary Fig. S1C)
Summary
Epigenetic changes, including histone modifications, often occur in cancer [1]. Among the post-translational modifications of histones, one regards the acetylation of specific lysine e-amino groups in the N-terminal tail of the Authors' Affiliations: 1Experimental Chemotherapy Laboratory and 2Molecular Oncogenesis Laboratory, Regina Elena National Cancer Institute; Departments of 3Anatomy, Histology, Forensic Medicine, Orthopedics, Section of Histology and Medical Embryology, 4Chemistry and Pharmaceutical Technologies, 5Chemistry and 6Institute of Molecular Biology and Pathology, CNR, "Sapienza" University; 7Institute of Cell Biology and Neurobiology-CNR Santa Lucia Foundation-IRCCS; and 8Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanita, Rome, ItalyNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2011 American Association for Cancer Research.core chromosomal histones H2A, H2B, H3, and H4. Epigenetic changes, including histone modifications, often occur in cancer [1]. The histone acetylation–deacetylation balance is accurately maintained through an equilibrium of HAT and HDAC enzymatic activities in normal cells. Irregular pattern of histone acetylation is often found associated with cancer, and it has been hypothesized to modulate the expression of oncogenes and tumor suppressor genes [9,10,11,12]. Both protein acetylation and deacetylation pathways represent attractive targets for cancer therapy. Translocation of HAT genes [15], mutation of the HAT p300 [16], overexpression of AIB-1, a HAT coactivator of a nuclear hormone receptor [17], represent www.aacrjournals.org
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