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Please use this identifier to cite or link to this item: http://hdl.handle.net/10805/2326

Title: CPTH6,an histone acetyltransferase, shows anti-tumor properties
Authors: RAGAZZONI, YLENIA
Tutor: Del Bufalo, Donatella
Ziparo, Elio
Keywords: cancer
histone acetyltransferase inhibitor
apoptosis
autophagy
Issue Date: 14-Feb-2014
Abstract: Recent studies strongly support the histone acetylation as a promising therapeutic target. Although a growing body of evidence demonstrates a direct relationship between histone acetyltransferases (HAT) activity and development or progression of cancer disease, only limited progress has been made in the field of HAT inhibitors. This study identifies the thiazole derivative 3-methyl-cyclopentylidene-[4-(4’-chlorophenyl)thiazol-2yl)hydrazone (CPTH6) as a novel HAT inhibitor in a panel of solid and hematologic tumor cell lines. CPTH6 leads to an inhibition of Gcn5 and pCAF HAT activity. Moreover, it inhibits H3/H4 histones and α-tubulin acetylation of acute myeloid leukemia cell (AML) line U-937. Concentration- and time-dependent inhibition of cell viability, paralleled by accumulation of cells in the G0/G1 phase and depletion from the S/G2M 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 over-expression 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. Moreover, CPTH6 treatment induced, in a dose-dependent manner, a significant increase of the membrane-bound form of microtubule-associated protein 1 light chain 3 (LC3B-II) levels and the appearance of typical LC3B-II-associated autophagosomal puncta. We found that the effect of CPTH6 on autophagy developed through a non-canonical mechanism that did not require beclin-1-dependent nucleation, but involved Atg-7-mediated elongation of autophagosomal membranes. Strikingly, a combined treatment of CPTH6 with late-stage autophagy inhibitors, such as chloroquine and bafilomycin A1, demonstrates that under basal condition CPTH6 reduces autophagosome turnover through an impairment of their degradation pathway. According to these results, CPTH6 induced enhancement of autophagy substrate p62 and NBR1 protein levels confirms a blockage of autophagic cargo degradation. In addition, CPTH6 inhibited autophagosome maturation and compounds having high structural similarities with CPTH6 produced similar effects on the autophagic pathway. Finally, the evidence that CPTH6 treatment decreased α-tubulin acetylation and failed to increase autophagic markers in cells in which acetyltransferase ATAT1 expression was silenced indicates a possible role of α-tubulin acetylation in CPTH6-induced alteration in autophagy. Overall, CPTH6 could be a valuable agent for the treatment of cancer and should be further studied as a possible antineoplastic agent.
URI: http://hdl.handle.net/10805/2326
Appears in PhD:SCIENZE E TECNOLOGIE CELLULARI

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