<p>Histone deacetylase inhibitors reinforce the phenotypical markers of breast epithelial or mesenchymal cancer cells but inhibit their migratory properties</p>

Abstract

IntroductionHistone deacetylase inhibitors (HDIs) are a group of compounds that exhibit anticancer activity, but their significance and usefulness in breast cancer (BC) treatment are still controversial. The ability of cancer cells to invade and migrate is augmented by the acquisition of a mesenchymal phenotype – a process known as epithelial-to-mesenchymal transition (EMT). Changes in the expression level of different cadherins, so-called cadherin switches, have been used to monitor the EMT process in development and tumor progression, in particular migration and invasion potential. The aim of this study was to analyze the influence of two HDIs – valproic acid (VPA) and vorinostat (SAHA) – on the migration potential of different BC cell types, as well as on EMT, or its reverse process – mesenchymal-to-epithelial transition, progression by means of shift in epithelial and mesenchymal marker expression.MethodsHDI treatment-induced expression of E- and N-cadherin at the mRNA and protein levels was evaluated by qPCR, Western blotting and immunostaining methods, respectively. BC cell proliferation and migration were assessed by BrdU, xCELLigence system and wound-healing assay.ResultsVPA and SAHA inhibited the proliferation and migration in a dose- and time-dependent manner, regardless of the BC cell type. Unawares, BC cells having a more mesenchymal phenotype (MDA-MB-468) were found to overexpress N-cadherin, whereas BC lines having an epithelial phenotype (T47D, MCF7) responded to HDI treatment by a significant increase of E-cadherin expression.DiscussionWe suggest that HDAC inhibition results in a more relaxed chromatin concomitant to an increase in the expression of already expressing genes.ConclusionBy using multiple cancer cell lines, we conclude that HDI induction or reversal of EMT is not a universal mechanism, yet inhibition of cell migration is, and thus EMT should not be considered as the only measurement for tumor aggressiveness.

Vorinostat (SAHA) and Breast Cancer: An Overview

“…Although SAHA inhibited migration and proliferation of all analyzed BC cells in a time- and dose-dependent fashion, MDA-MB-468 cells with a more mesenchymal phenotype were found to overexpress mesenchymal markers (e.g., N-cadherin), whereas epithelial phenotype BC cells (T47D, MCF7) responded to SAHA treatment by an increase of epithelial markers (e.g., E-cadherin) expression. Therefore, induction of EMT or MET by SAHA is not a universal mechanism but cells- and context-dependent, and thus EMT should not be considered as the only measurement for tumor aggressiveness in BC ( Table 2 ) [ 111 ].…”

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

“…We also demonstrated additive type of pharmacological interactions between CDDP and SAHA or VPA at the fixed-ratio combination of 1:1 in TNBC cancer cell lines with increased or decreased Notch1 activity [ 18 ]. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was used to evaluate antiproliferative effect of HDIs/CDDP treatment in the BC in vitro models, although previously [ 22 , 23 ] we showed by other methods the results of these drugs individually or/and in combinations on apoptosis [ 22 ], cell cycle arrest [ 22 ], and BrdU incorporation [ 23 ].…”

Valproic Acid and Breast Cancer: State of the Art in 2021

“…However, BC cells with the more mesenchymal phenotype (MDA-MB-468) were found to overexpress N-cadherin, whereas BC lines with an epithelial phenotype (T47D, MCF7) responded to HDI treatment through a significant increase in E-cadherin expression. Therefore, the authors conclude that HDI induction or reversal of EMT is not a universal mechanism, yet inhibition of cell migration is, and thus EMT should not be considered as the only measurement for tumor aggressiveness [ 64 ]. Taking into account the very divergent results regarding the influence of VPA on the EMT process this phenomenon should be thoroughly re-examined using the entire panel of BC cell lines and in vivo models ( Table 3 ).…”