Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells

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dc.authoridEngin Ulukaya / 0000-0003-4875-5472en_US
dc.authoridNazlıhan Aztopal / 0000-0003-3118-8061en_US
dc.authoridMerve Erkısa Genel / 0000-0002-3127-742X
dc.authorscopusidNazlıhan Aztopal / 55853882900
dc.authorscopusidMerve Erkısa / 57126208900
dc.authorscopusidEngin Ulukaya / 6602927353
dc.authorwosidNazlıhan Aztopal / L-6687-2018
dc.authorwosidEngin Ulukaya / K-5792-2018
dc.authorwosidMerve Erkısa / AAM-1001-2020
dc.contributor.authorAztopal, Nazlıhan
dc.contributor.authorErkısa Genel, Merve
dc.contributor.authorErtürk, Elif
dc.contributor.authorUlukaya, Engin
dc.contributor.authorTokullugil, Asuman Hatice
dc.contributor.authorArı, Ferda
dc.date.accessioned2020-08-30T20:07:43Z
dc.date.available2020-08-30T20:07:43Z
dc.date.issued2018
dc.departmentİstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümüen_US
dc.description.abstractCancer stem-like cells (CSCs) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, give rise to metastases and lead to disease relapse because of an acquired resistance to apoptosis. Especially, epigenetic alterations play a crucial role in the regulation of stemness and also have been implicated in the development of drug resistance. Hence, in the present study, we examined the cytotoxic and apoptotic activity of valproic acid (VPA) as an inhibitor of histone deacetylases (HDACs) against breast CSCs (BCSCs). Increased expression of stemness markers were determined by western blotting in mammospheres (MCF-7s, a cancer stem cell-enriched population) propagated from parental MCF-7 cells. Anti-growth activity of VPA was determined via ATP viability assay. The sphere formation assay (SFA) was performed to assess the inhibitory effect of VPA on the self-renewal capacity of MCF-7s cells. Acetylation of histon H3 was detected with ELISA assay. Cell death mode was performed by Hoechst dye 33342 and propidium iodide-based flouresent stainings (for pyknosis and membrane integrity), by M30 and M65 ELISA assays (for apoptosis and primary or secondary necrosis) as well as cyto-fluorimetric analysis (caspase 3/7 activity and annexin-V-FITC staining for early and late stage apoptosis). VPA exhibited anti-growth effect against both MCF-7 and MCF-7s cells in a dose (0.6-20 mM) and time (24, 48, 72 h) dependent manner. As expected, MCF-7s cells were found more resistant to VPA than MCF-7 cells. It was observed that VPA prevented mammosphere formation at relatively lower doses (2.5 and 5 mM) while the acetylation of histon H3 was increased. At the same doses, VPA increased the M30 levels, annexin-V-FITC positivity and caspase 3/7 activation, implying the induction of apoptosis. The secondary necrosis (late stage of apoptosis) was also evidenced by nuclear pyknosis with propidium iodide staining positivity. Taken together, inhibition of HDACs is cytotoxic to BCSCs by apoptosis. Our results suggested that targeting the epigenetic regulation of histones may be a novel approach and hold significant promise for successful treatment of breast cancer.en_US
dc.description.sponsorshipUludag University (Bursa, Turkey)Uludag University [KUAP(T)-2015/6]en_US
dc.description.sponsorshipThis work was supported by the Research Fund of Uludag University (Bursa, Turkey) for the project that is numbered KUAP(T)-2015/6.en_US
dc.identifier.citationAztopal, N., Erkisa, M., Erturk, E., Ulukaya, E., Tokullugil, A. H., & Ari, F. (2018). Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chemico-Biological Interactions, 280, 51–58. https://doi.org/10.1016/j.cbi.2017.12.003en_US
dc.identifier.doi10.1016/j.cbi.2017.12.003en_US
dc.identifier.endpage58en_US
dc.identifier.issn0009-2797en_US
dc.identifier.issn1872-7786en_US
dc.identifier.pmid29225137en_US
dc.identifier.scopus2-s2.0-85037667087en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage51en_US
dc.identifier.urihttps://doi.org/10.1016/j.cbi.2017.12.003
dc.identifier.urihttps://hdl.handle.net/20.500.12713/819
dc.identifier.volume280en_US
dc.identifier.wosWOS:000419835000007en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorAztopal, Nazlıhanen_US
dc.institutionauthorErkısa Genel, Merveen_US
dc.institutionauthorUlukaya, Enginen_US
dc.language.isoenen_US
dc.publisherElsevier Ireland Ltden_US
dc.relation.ispartofChemico-Biological Interactionsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectValproic Aciden_US
dc.subjectEpigenetic Modulatorsen_US
dc.subjectApoptosisen_US
dc.subjectBreast Cancer Stem Cellen_US
dc.titleValproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cellsen_US
dc.typeArticleen_US

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