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

Authors Wawruszak A, Gumbarewicz E, Okon E, Jeleniewicz W, Czapinski J, Halasa M, Okla K, Smok-Kalwat J, Bocian A, Rivero-Muller A, Stepulak A

Received 26 March 2019

Accepted for publication 4 September 2019

Published 13 September 2019 Volume 2019:11 Pages 8345—8358

DOI https://doi.org/10.2147/CMAR.S210029

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Anna Wawruszak,1 Ewelina Gumbarewicz,1 Estera Okon,1 Witold Jeleniewicz,1 Jakub Czapinski,1,2 Marta Halasa,1 Karolina Okla,3,4 Jolanta Smok-Kalwat,5 Artur Bocian,6 Adolfo Rivero-Muller,1,7,* Andrzej Stepulak1,*

1Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland; 2School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland; 3The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland; 4Tumor Immunology Laboratory, Medical University of Lublin, Lublin, Poland; 5Department of Clinical Oncology, Holy Cross Cancer Centre, Kielce, Poland; 6Department of Oncological Surgery, Holy Cross Cancer Centre, Kielce, Poland; 7Faculty of Science and Engineering, Cell Biology, Abo Akademi University, Turku, Finland

*These authors contributed equally to this work

Correspondence: Andrzej Stepulak; Adolfo Rivero-Muller
Department of Biochemistry and Molecular Biology, Medical University of Lublin, Chodzki 1, Lublin 20-093, Poland
Tel +48 81 448 6350
Fax +48 81 448 6350
Email andrzej.stepulak@umlub.pl; adolfo.rivero-muller@umlub.pl

Introduction: Histone 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.
Methods: HDI 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.
Results: VPA 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.
Discussion: We suggest that HDAC inhibition results in a more relaxed chromatin concomitant to an increase in the expression of already expressing genes.
Conclusion: By 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.

Keywords: breast cancer, HDIs, VPA, SAHA, EMT, migration


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