{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:47:42Z","timestamp":1790552862118,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,3,30]],"date-time":"2019-03-30T00:00:00Z","timestamp":1553904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.<\/jats:p>","DOI":"10.3390\/ijms20071601","type":"journal-article","created":{"date-parts":[[2019,4,2]],"date-time":"2019-04-02T03:21:26Z","timestamp":1554175286000},"page":"1601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7861-9132","authenticated-orcid":false,"given":"Ping","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkui","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s12032-014-0985-5","article-title":"Histone deacetylase inhibitors in glioblastoma: Pre-clinical and clinical experience","volume":"31","author":"Bezecny","year":"2014","journal-title":"Med. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10549-004-1668-2","article-title":"Histone deacetylase-1 and -3 protein expression in human breast cancer: A tissue microarray analysis","volume":"90","author":"Krusche","year":"2005","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.lungcan.2011.02.019","article-title":"Expression of histone deacetylase 1 correlates with a poor prognosis in patients with adenocarcinoma of the lung","volume":"74","author":"Minamiya","year":"2011","journal-title":"Lung Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1159\/000111106","article-title":"Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma","volume":"72","author":"Rikimaru","year":"2007","journal-title":"Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S1470-2045(08)70004-4","article-title":"Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: A retrospective analysis","volume":"9","author":"Weichert","year":"2008","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/sj.bjc.6604199","article-title":"Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy","volume":"98","author":"Weichert","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1158\/1078-0432.CCR-07-0990","article-title":"Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class I histone deacetylases in vitro and in vivo","volume":"14","author":"Weichert","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1016\/j.urolonc.2012.06.015","article-title":"Changes in histone deacetylase (HDAC) expression patterns and activity of HDAC inhibitors in urothelial cancers","volume":"31","author":"Niegisch","year":"2013","journal-title":"Urol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1172\/JCI69738","article-title":"New and emerging HDAC inhibitors for cancer treatment","volume":"124","author":"West","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Singh, A.K., Bishayee, A., and Pandey, A.K. (2018). Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy. Nutrients, 10.","DOI":"10.3390\/nu10060731"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fonc.2018.00092","article-title":"Combination Therapy with Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi","volume":"8","author":"Suraweera","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wawruszak, A., Kalafut, J., Okon, E., Czapinski, J., Halasa, M., Przybyszewska, A., Miziak, P., Okla, K., Rivero-Muller, A., and Stepulak, A. (2019). Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells. Cancers, 11.","DOI":"10.3390\/cancers11020148"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.gene.2005.09.010","article-title":"Acetylation and deacetylation of non-histone proteins","volume":"363","author":"Glozak","year":"2005","journal-title":"Gene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.molcel.2008.07.002","article-title":"Lysine acetylation: Codified crosstalk with other posttranslational modifications","volume":"31","author":"Yang","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrd1930","article-title":"Epigenetic therapy of cancer: Past, present and future","volume":"5","author":"Yoo","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S1097-2765(04)00094-2","article-title":"Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis","volume":"13","author":"Cohen","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S1097-2765(02)00431-8","article-title":"DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes","volume":"9","author":"Costanzo","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/sj.cdd.4401567","article-title":"Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1\/WAF1 expression, independent of histone deacetylase 1","volume":"12","author":"Huang","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Olaharski, A.J., Rine, J., Marshall, B.L., Babiarz, J., Zhang, L., Verdin, E., and Smith, M.T. (2005). The flavoring agent dihydrocoumarin reverses epigenetic silencing and inhibits sirtuin deacetylases. PLoS Genet., 1.","DOI":"10.1371\/journal.pgen.0010077"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4137\/JCD.S13695","article-title":"Regulation of ku70-bax complex in cells","volume":"7","author":"Hada","year":"2014","journal-title":"J. Cell Death"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1126\/science.272.5260.408","article-title":"A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p","volume":"272","author":"Taunton","year":"1996","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/sj.onc.1210620","article-title":"Histone deacetylase inhibitors: Molecular mechanisms of action","volume":"26","author":"Xu","year":"2007","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/bjc.2013.21","article-title":"Histone deacetylase inhibitors as radiosensitisers: Effects on DNA damage signalling and repair","volume":"108","author":"Groselj","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev.biochem.73.011303.073651","article-title":"The Sir2 family of protein deacetylases","volume":"73","author":"Blander","year":"2004","journal-title":"Annu. Rev. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrd2133","article-title":"Anticancer activities of histone deacetylase inhibitors","volume":"5","author":"Bolden","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.bbagrm.2008.06.005","article-title":"Chemical mechanisms of histone lysine and arginine modifications","volume":"1789","author":"Smith","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1101\/gad.14.2.121","article-title":"The coregulator exchange in transcriptional functions of nuclear receptors","volume":"14","author":"Glass","year":"2000","journal-title":"Genes Dev."},{"key":"ref_28","first-page":"5355","article-title":"Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?","volume":"37","author":"Garmpis","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1586\/era.10.62","article-title":"Nonhistone protein acetylation as cancer therapy targets","volume":"10","author":"Singh","year":"2010","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1093\/emboj\/20.6.1331","article-title":"p300\/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2","volume":"20","author":"Ito","year":"2001","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.cell.2008.03.025","article-title":"Acetylation is indispensable for p53 activation","volume":"133","author":"Tang","year":"2008","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1007\/s13238-011-1063-9","article-title":"The impact of acetylation and deacetylation on the p53 pathway","volume":"2","author":"Brooks","year":"2011","journal-title":"Protein Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/35042612","article-title":"Deacetylation of p53 modulates its effect on cell growth and apoptosis","volume":"408","author":"Luo","year":"2000","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0092-8674(01)00524-4","article-title":"Negative control of p53 by Sir2alpha promotes cell survival under stress","volume":"107","author":"Luo","year":"2001","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0092-8674(01)00527-X","article-title":"hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase","volume":"107","author":"Vaziri","year":"2001","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/j.febslet.2013.02.001","article-title":"HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity","volume":"587","author":"Ding","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mrakovcic, M., Bohner, L., Hanisch, M., and Frohlich, L.F. (2018). Epigenetic Targeting of Autophagy via HDAC Inhibition in Tumor Cells: Role of p53. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123952"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6845","DOI":"10.1038\/sj.onc.1203224","article-title":"Regulation of DNA binding by Rel\/NF-kappaB transcription factors: Structural views","volume":"18","author":"Chen","year":"1999","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1042\/BST0350281","article-title":"Impact of post-translational modifications of proteins on the inflammatory process","volume":"35","author":"Ito","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1126\/science.1062374","article-title":"Duration of nuclear NF-kappaB action regulated by reversible acetylation","volume":"293","author":"Chen","year":"2001","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7065","DOI":"10.1128\/MCB.21.20.7065-7077.2001","article-title":"The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression","volume":"21","author":"Ashburner","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5409","DOI":"10.1158\/0008-5472.CAN-05-4225","article-title":"Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappaB by tumor necrosis factor-alpha receptor-1 down-regulation","volume":"66","author":"Imre","year":"2006","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5612","DOI":"10.1074\/jbc.M507213200","article-title":"Suberoylanilide hydroxamic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing nuclear factor-kappaB activation","volume":"281","author":"Takada","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1126\/science.1068408","article-title":"Molecular chaperones in the cytosol: From nascent chain to folded protein","volume":"295","author":"Hartl","year":"2002","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1535-6108(03)00029-1","article-title":"Heat shock protein 90 as a molecular target for cancer therapeutics","volume":"3","author":"Isaacs","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_46","first-page":"1799","article-title":"Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts","volume":"61","author":"Nimmanapalli","year":"2001","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1158\/0008-5472.CAN-04-0006","article-title":"Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3","volume":"64","author":"George","year":"2004","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1158\/1535-7163.1021.3.8","article-title":"Altered Hsp90 function in cancer: A unique therapeutic opportunity","volume":"3","author":"Bagatell","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.tips.2014.08.001","article-title":"Drugging the HDAC6-HSP90 interplay in malignant cells","volume":"35","author":"Kramer","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1182\/blood-2004-09-3413","article-title":"Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3","volume":"105","author":"George","year":"2005","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.18632\/oncotarget.2154","article-title":"Histone deacetylase inhibitor treatment induces \u2018BRCAness\u2019 and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells","volume":"5","author":"Ha","year":"2014","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm909","article-title":"Stats: Transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1126\/science.277.5332.1630","article-title":"STATs and gene regulation","volume":"277","author":"Darnell","year":"1997","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1038\/leu.2011.340","article-title":"Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: Implications for therapy","volume":"26","author":"Gupta","year":"2012","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"ra46","DOI":"10.1126\/scisignal.2001465","article-title":"The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy","volume":"4","author":"Sundaresan","year":"2011","journal-title":"Sci. Signal."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1161\/CIRCRESAHA.113.300536","article-title":"Regulation of Akt signaling by sirtuins: Its implication in cardiac hypertrophy and aging","volume":"114","author":"Pillai","year":"2014","journal-title":"Circ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1021\/acschembio.6b01014","article-title":"Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells","volume":"12","author":"Iaconelli","year":"2017","journal-title":"ACS Chem. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1038\/leu.2017.130","article-title":"Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response","volume":"31","author":"Long","year":"2017","journal-title":"Leukemia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1016\/j.cellsig.2013.06.007","article-title":"Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders","volume":"25","author":"Kauppinen","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1242\/jcs.073783","article-title":"SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310","volume":"123","author":"Rothgiesser","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12974-018-1193-6","article-title":"Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-kappaB pathway dependent of HDAC3","volume":"15","author":"Chen","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/s41419-018-0602-1","article-title":"HDAC and Ku70 axis- an effective target for apoptosis induction by a new 2-cyano-3-oxo-1,9-dien glycyrrhetinic acid analogue","volume":"9","author":"Gong","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_63","first-page":"225","article-title":"Maspin increases Ku70 acetylation and Bax-mediated cell death in cancer cells","volume":"29","author":"Lee","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1593\/neo.11558","article-title":"HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma","volume":"13","author":"Subramanian","year":"2011","journal-title":"Neoplasia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"50195","DOI":"10.18632\/oncotarget.10328","article-title":"SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells","volume":"7","author":"Roth","year":"2016","journal-title":"Oncotarget"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6384","DOI":"10.1128\/MCB.00426-08","article-title":"SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70","volume":"28","author":"Sundaresan","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.bbrc.2017.02.111","article-title":"Deacetylation of Ku70 by SIRT6 attenuates Bax-mediated apoptosis in hepatocellular carcinoma","volume":"485","author":"Tao","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6820","DOI":"10.1093\/emboj\/cdf682","article-title":"In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation","volume":"21","author":"Matsuyama","year":"2002","journal-title":"EMBO J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S1097-2765(03)00038-8","article-title":"The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase","volume":"11","author":"North","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s41556-018-0047-x","article-title":"NCoR\/SMRT co-repressors cooperate with c-MYC to create an epigenetic barrier to somatic cell reprogramming","volume":"20","author":"Zhuang","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12686","DOI":"10.1074\/jbc.C700185200","article-title":"HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization","volume":"283","author":"Li","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Chang, C.C., Sue, Y.M., Yang, N.J., Lee, Y.H., and Juan, S.H. (2014). 3-Methylcholanthrene, an AhR agonist, caused cell-cycle arrest by histone deacetylation through a RhoA-dependent recruitment of HDAC1 and pRb2 to E2F1 complex. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092793"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/S0092-8674(02)01085-1","article-title":"Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation","volume":"111","author":"Jeong","year":"2002","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1007\/s11033-013-2996-2","article-title":"VPA inhibits renal cancer cell migration by targeting HDAC2 and down-regulating HIF-1alpha","volume":"41","author":"Yang","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"38095","DOI":"10.1074\/jbc.M111.257055","article-title":"HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia","volume":"286","author":"Geng","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1010428317705034","DOI":"10.1177\/1010428317705034","article-title":"Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1alpha under hypoxia condition","volume":"39","author":"Ye","year":"2017","journal-title":"Tumour Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/ijc.11403","article-title":"Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor alpha","volume":"107","author":"Kawai","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1021\/cb500838r","article-title":"HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of beta-catenin in human iPSC-derived neuronal cells","volume":"10","author":"Iaconelli","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1182\/blood.V98.7.2116","article-title":"Histone deacetylase 3 associates with and represses the transcription factor GATA-2","volume":"98","author":"Ozawa","year":"2001","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"9176","DOI":"10.1038\/sj.onc.1206902","article-title":"Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation","volume":"22","author":"Watamoto","year":"2003","journal-title":"Oncogene"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"28873","DOI":"10.1074\/jbc.M401138200","article-title":"FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)","volume":"279","author":"Tertoolen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/hepr.12757","article-title":"Histone deacetylases function as novel potential therapeutic targets for cancer","volume":"47","author":"Zhang","year":"2017","journal-title":"Hepatol. Res."},{"key":"ref_83","first-page":"1247","article-title":"FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma","volume":"12","author":"Mann","year":"2007","journal-title":"Oncology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1586\/era.10.88","article-title":"Romidepsin: A new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors","volume":"10","author":"Grant","year":"2010","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1177\/2040620715592567","article-title":"Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: A perspective review","volume":"6","author":"Sawas","year":"2015","journal-title":"Ther. Adv. Hematol."},{"key":"ref_86","first-page":"296","article-title":"Panobinostat (Farydak): A Novel Option for the Treatment of Relapsed Or Relapsed and Refractory Multiple Myeloma","volume":"41","author":"Moore","year":"2016","journal-title":"Pharm. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"185","DOI":"10.5582\/irdr.2016.01024","article-title":"Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China","volume":"5","author":"Lu","year":"2016","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1200\/JCO.2011.37.4223","article-title":"Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy","volume":"30","author":"Coiffier","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.ejca.2010.02.047","article-title":"Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours","volume":"46","author":"Mackay","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1007\/s10637-011-9751-0","article-title":"Phase I dose-escalating study of panobinostat (LBH589) administered intravenously to Japanese patients with advanced solid tumors","volume":"30","author":"Morita","year":"2012","journal-title":"Investig. New Drugs"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/1091581809352111","article-title":"Nonclinical safety assessment of the histone deacetylase inhibitor vorinostat","volume":"29","author":"Kerr","year":"2010","journal-title":"Int. J. Toxicol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/cmdc.201500486","article-title":"Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors--What Some May Have Forgotten or Would Rather Forget?","volume":"11","author":"Shen","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"551","DOI":"10.3390\/molecules23030551","article-title":"The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors","volume":"23","author":"Cao","year":"2018","journal-title":"Molecules"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.bcp.2012.06.014","article-title":"Development and therapeutic impact of HDAC6-selective inhibitors","volume":"84","author":"Dallavalle","year":"2012","journal-title":"Biochem. Pharm."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13148-018-0531-y","article-title":"Effects of novel HDAC inhibitors on urothelial carcinoma cells","volume":"10","author":"Kaletsch","year":"2018","journal-title":"Clin. Epigenet."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Manzotti, G., Ciarrocchi, A., and Sancisi, V. (2019). Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers, 11.","DOI":"10.3390\/cancers11030304"},{"key":"ref_97","first-page":"166","article-title":"Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anti-cancer drugs","volume":"3","author":"Kim","year":"2011","journal-title":"Am. J. Transl. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrc1779","article-title":"Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer","volume":"6","author":"Minucci","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"514261","DOI":"10.1155\/2011\/514261","article-title":"Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors","volume":"2011","author":"Miller","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1084\/jem.192.8.F21","article-title":"Cross-talk in cell death signaling","volume":"192","author":"Roy","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1002\/ijc.24064","article-title":"Tumor resistance to apoptosis","volume":"124","author":"Fulda","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1126\/science.1190217","article-title":"BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program","volume":"330","author":"Ren","year":"2010","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1177\/1947601911417177","article-title":"The Role of BH3-Only Proteins in Tumor Cell Development, Signaling, and Treatment","volume":"2","author":"Elkholi","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/B978-0-12-394387-3.00005-7","article-title":"Intrinsic and extrinsic apoptotic pathway signaling as determinants of histone deacetylase inhibitor antitumor activity","volume":"116","author":"Matthews","year":"2012","journal-title":"Adv. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1182\/blood-2013-11-538819","article-title":"SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia","volume":"124","author":"Sasca","year":"2014","journal-title":"Blood"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1038\/onc.2010.599","article-title":"Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation","volume":"30","author":"Hacker","year":"2011","journal-title":"Oncogene"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.leukres.2011.04.004","article-title":"Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells","volume":"35","author":"Nishioka","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"7762","DOI":"10.1038\/sj.onc.1207091","article-title":"p53-independent induction of Gadd45 by histone deacetylase inhibitor: Coordinate regulation by transcription factors Oct-1 and NF-Y","volume":"22","author":"Hirose","year":"2003","journal-title":"Oncogene"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"7016","DOI":"10.1038\/sj.onc.1203176","article-title":"Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2\/Bcl-XL, c-Jun, and p21CIP1, but independent of p53","volume":"18","author":"Vrana","year":"1999","journal-title":"Oncogene"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.1038\/s41598-017-04874-4","article-title":"HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension","volume":"7","author":"Boucherat","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3892\/mmr.2015.3358","article-title":"Ku70 is essential for histone deacetylase inhibitor trichostatin A-induced apoptosis","volume":"12","author":"Meng","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.dnarep.2006.05.026","article-title":"Role of non-homologous end joining (NHEJ) in maintaining genomic integrity","volume":"5","author":"Burma","year":"2006","journal-title":"DNA Repair"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1593\/neo.09720","article-title":"A nonhomologous end-joining pathway is required for protein phosphatase 2A promotion of DNA double-strand break repair","volume":"11","author":"Wang","year":"2009","journal-title":"Neoplasia"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1593\/neo.121258","article-title":"c-Myc suppression of DNA double-strand break repair","volume":"14","author":"Li","year":"2012","journal-title":"Neoplasia"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"13903","DOI":"10.1007\/s13277-016-5202-z","article-title":"Cytosolic Ku70 regulates Bax-mediated cell death","volume":"37","author":"Hada","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ceb.2006.10.004","article-title":"How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane?","volume":"18","author":"Antignani","year":"2006","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4842","DOI":"10.1073\/pnas.0408351102","article-title":"Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e1706","DOI":"10.1038\/cddis.2015.11","article-title":"Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases","volume":"6","author":"Ngo","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1177\/1535370216654587","article-title":"Bax-induced apoptosis shortens the life span of DNA repair defect Ku70-knockout mice by inducing emphysema","volume":"241","author":"Matsuyama","year":"2016","journal-title":"Exp. Biol. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1093\/hmg\/ddp399","article-title":"Ku70 regulates Bax-mediated pathogenesis in laminin-alpha2-deficient human muscle cells and mouse models of congenital muscular dystrophy","volume":"18","author":"Vishnudas","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1073\/pnas.0706700105","article-title":"Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation","volume":"105","author":"Amsel","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.4161\/cc.8.12.8864","article-title":"DeubiKuitylation: A novel DUB enzymatic activity for the DNA repair protein, Ku70","volume":"8","author":"Rathaus","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tcb.2012.08.011","article-title":"Delving deeper: MCL-1\u2019s contributions to normal and cancer biology","volume":"23","author":"Perciavalle","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1038\/cdd.2014.42","article-title":"Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis","volume":"21","author":"Wang","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/cdd.2012.8","article-title":"Identification of an acetylation-dependant Ku70\/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis","volume":"19","author":"Kerr","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/bjh.12108","article-title":"Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia","volume":"160","author":"McLornan","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/s41419-018-1125-5","article-title":"Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists","volume":"9","author":"McCann","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"13538","DOI":"10.18632\/oncotarget.6455","article-title":"SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.18632\/oncotarget.23386","article-title":"Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells","volume":"9","author":"Valdez","year":"2018","journal-title":"Oncotarget"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.leukres.2016.03.007","article-title":"Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin","volume":"45","author":"Robert","year":"2016","journal-title":"Leuk. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3892\/or.2015.4089","article-title":"Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells","volume":"34","author":"Makita","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1158\/1535-7163.MCT-08-0385","article-title":"Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824\/fludarabine antileukemic interactions","volume":"7","author":"Rosato","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_133","first-page":"117","article-title":"Sensitization of suberoylanilide hydroxamic acid (SAHA) on chemoradiation for human cervical cancer cells and its mechanism","volume":"36","author":"Xing","year":"2015","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/mt.2009.227","article-title":"Amphiregulin promotes resistance to gefitinib in nonsmall cell lung cancer cells by regulating Ku70 acetylation","volume":"18","author":"Busser","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00018-014-1727-8","article-title":"Selective class IIa HDAC inhibitors: Myth or reality","volume":"72","author":"Gagliostro","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.tcb.2008.04.003","article-title":"HDAC6: A key regulator of cytoskeleton, cell migration and cell-cell interactions","volume":"18","author":"Cabrero","year":"2008","journal-title":"Trends Cell Biol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/j.ejmech.2018.08.081","article-title":"HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR\/QSAR\/QAAR approaches","volume":"157","author":"Adhikari","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1042\/BJ20070779","article-title":"Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors","volume":"409","author":"Khan","year":"2008","journal-title":"Biochem. J."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1182\/blood-2009-07-235663","article-title":"Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma","volume":"116","author":"Kikuchi","year":"2010","journal-title":"Blood"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s10549-013-2542-x","article-title":"Clinicopathological significance of KU70\/KU80, a key DNA damage repair protein in breast cancer","volume":"139","author":"Alshareeda","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.prp.2015.12.012","article-title":"The DNA damage repair protein Ku70 regulates tumor cell and hepatic carcinogenesis by interacting with FOXO4","volume":"212","author":"Zhang","year":"2016","journal-title":"Pathol. Res. Pract."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1601\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:41:46Z","timestamp":1760186506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,30]]},"references-count":141,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071601"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071601","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,30]]}}}