{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T16:02:48Z","timestamp":1793980968705,"version":"4.8.0"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T00:00:00Z","timestamp":1578873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2010.078"],"award-info":[{"award-number":["2010.078"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DFG","award":["#KR2291\/7-1\/8-1\/9-1"],"award-info":[{"award-number":["#KR2291\/7-1\/8-1\/9-1"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-\u03b2 (TGF\u03b2). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGF\u03b2-induced cellular plasticity of transformed cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>HDACi suppress the epithelial\u2013mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-019-03118-4","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T08:02:43Z","timestamp":1578902563000},"page":"343-356","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes"],"prefix":"10.1007","volume":"146","author":[{"given":"Nicole","family":"Kiweler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9sir\u00e9e","family":"W\u00fcnsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisintha","family":"Mahendrarajah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland H.","family":"Stauber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walburgis","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falk","family":"Butter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-045X","authenticated-orcid":false,"given":"Oliver H.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,13]]},"reference":[{"key":"3118_CR1","doi-asserted-by":"publisher","first-page":"E7","DOI":"10.1038\/nature22963","volume":"547","author":"NM Aiello","year":"2017","unstructured":"Aiello NM, Brabletz T, Kang Y et al (2017) Upholding a role for EMT in pancreatic cancer metastasis. Nature 547:E7\u2013E8. https:\/\/doi.org\/10.1038\/nature22963","journal-title":"Nature"},{"key":"3118_CR2","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.eururo.2016.08.024","volume":"71","author":"CE Barbieri","year":"2017","unstructured":"Barbieri CE, Chinnaiyan AM, Lerner SP et al (2017) The emergence of precision urologic oncology: a collaborative review on biomarker-driven therapeutics. Eur Urol 71:237\u2013246. https:\/\/doi.org\/10.1016\/j.eururo.2016.08.024","journal-title":"Eur Urol"},{"key":"3118_CR3","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1038\/onc.2013.141","volume":"33","author":"C Barckhausen","year":"2014","unstructured":"Barckhausen C, Roos WP, Naumann SC, Kaina B (2014) Malignant melanoma cells acquire resistance to DNA interstrand cross-linking chemotherapeutics by p53-triggered upregulation of DDB2\/XPC-mediated DNA repair. Oncogene 33:1964\u20131974. https:\/\/doi.org\/10.1038\/onc.2013.141","journal-title":"Oncogene"},{"key":"3118_CR4","doi-asserted-by":"publisher","first-page":"38022","DOI":"10.18632\/oncotarget.16723","volume":"8","author":"R Bayat Mokhtari","year":"2017","unstructured":"Bayat Mokhtari R, Homayouni TS, Baluch N et al (2017) Combination therapy in combating cancer. Oncotarget 8:38022\u201338043. https:\/\/doi.org\/10.18632\/oncotarget.16723","journal-title":"Oncotarget"},{"key":"3118_CR5","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/nrc.2017.118","volume":"18","author":"T Brabletz","year":"2018","unstructured":"Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nature reviews. Cancer 18:128\u2013134. https:\/\/doi.org\/10.1038\/nrc.2017.118","journal-title":"Cancer"},{"key":"3118_CR6","doi-asserted-by":"publisher","first-page":"12617","DOI":"10.1073\/pnas.1006774107","volume":"107","author":"JE Bradner","year":"2010","unstructured":"Bradner JE, Mak R, Tanguturi SK et al (2010) Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci USA 107:12617\u201312622. https:\/\/doi.org\/10.1073\/pnas.1006774107","journal-title":"Proc Natl Acad Sci USA"},{"key":"3118_CR7","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1093\/jmcb\/mjs013","volume":"4","author":"A Brandl","year":"2012","unstructured":"Brandl A, Wagner T, Uhlig KM et al (2012) Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress. J Mol Cell Biol 4:284\u2013293. https:\/\/doi.org\/10.1093\/jmcb\/mjs013","journal-title":"J Mol Cell Biol"},{"key":"3118_CR8","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1002\/cncr.21589","volume":"104","author":"G Bug","year":"2005","unstructured":"Bug G, Ritter M, Wassmann B et al (2005) Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 104:2717\u20132725. https:\/\/doi.org\/10.1002\/cncr.21589","journal-title":"Cancer"},{"key":"3118_CR9","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.21873\/anticanres.13393","volume":"39","author":"AJ Chang","year":"2019","unstructured":"Chang AJ, Zhao L, Zhu Z et al (2019) The past, present and future of immunotherapy for metastatic renal cell carcinoma. Anticancer Res 39:2683\u20132687. https:\/\/doi.org\/10.21873\/anticanres.13393","journal-title":"Anticancer Res"},{"key":"3118_CR10","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.molonc.2010.03.001","volume":"4","author":"BT Chua","year":"2010","unstructured":"Chua BT, Lim SJ, Tham SC et al (2010) Somatic mutation in the ACK1 ubiquitin association domain enhances oncogenic signaling through EGFR regulation in renal cancer derived cells. Mol Oncol 4:323\u2013334. https:\/\/doi.org\/10.1016\/j.molonc.2010.03.001","journal-title":"Mol Oncol"},{"key":"3118_CR11","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1007\/s12272-017-0998-7","volume":"41","author":"P Chun","year":"2018","unstructured":"Chun P (2018) Therapeutic effects of histone deacetylase inhibitors on kidney disease. Arch Pharmacal Res 41:162\u2013183. https:\/\/doi.org\/10.1007\/s12272-017-0998-7","journal-title":"Arch Pharmacal Res"},{"key":"3118_CR12","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.2217\/fon-2016-0526","volume":"13","author":"RM Connolly","year":"2017","unstructured":"Connolly RM, Rudek MA, Piekarz R (2017) Entinostat: a promising treatment option for patients with advanced breast cancer. Future Oncol 13:1137\u20131148. https:\/\/doi.org\/10.2217\/fon-2016-0526","journal-title":"Future Oncol"},{"key":"3118_CR13","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27916","author":"L Conradt","year":"2012","unstructured":"Conradt L, Henrich A, Wirth M et al (2012) Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death. Int J Cancer. https:\/\/doi.org\/10.1002\/ijc.27916","journal-title":"Int J Cancer"},{"key":"3118_CR14","doi-asserted-by":"publisher","first-page":"4470","DOI":"10.1158\/0008-5472.CAN-09-3028","volume":"70","author":"C Conti","year":"2010","unstructured":"Conti C, Leo E, Eichler GS et al (2010) Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage. Cancer Res 70:4470\u20134480. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-3028","journal-title":"Cancer Res"},{"key":"3118_CR15","doi-asserted-by":"publisher","first-page":"2202","DOI":"10.1158\/0008-5472.CAN-05-3560","volume":"66","author":"M Deckers","year":"2006","unstructured":"Deckers M, van Dinther M, Buijs J et al (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66:2202\u20132209. https:\/\/doi.org\/10.1158\/0008-5472.CAN-05-3560","journal-title":"Cancer Res"},{"key":"3118_CR16","doi-asserted-by":"publisher","first-page":"e1005439","DOI":"10.1371\/journal.ppat.1005439","volume":"12","author":"M Dejung","year":"2016","unstructured":"Dejung M, Subota I, Bucerius F et al (2016) Quantitative proteomics uncovers novel factors involved in developmental differentiation of Trypanosoma brucei. PLoS Pathog 12:e1005439. https:\/\/doi.org\/10.1371\/journal.ppat.1005439","journal-title":"PLoS Pathog"},{"key":"3118_CR17","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/978-3-319-40389-2_6","volume":"170","author":"MF Dietrich","year":"2016","unstructured":"Dietrich MF, Gerber DE (2016) Chemotherapy for advanced non-small cell lung cancer. Cancer Treat Res 170:119\u2013149. https:\/\/doi.org\/10.1007\/978-3-319-40389-2_6","journal-title":"Cancer Treat Res"},{"key":"3118_CR18","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/S0090-4295(99)00093-X","volume":"54","author":"JD Engel","year":"1999","unstructured":"Engel JD, Kundu SD, Yang T et al (1999) Transforming growth factor-beta type II receptor confers tumor suppressor activity in murine renal carcinoma (renca) cells. Urology 54:164\u2013170","journal-title":"Urology"},{"key":"3118_CR19","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1093\/bioinformatics\/btl567","volume":"23","author":"S Falcon","year":"2007","unstructured":"Falcon S, Gentleman R (2007) Using GOstats to test gene lists for GO term association. Bioinformatics 23:257\u2013258. https:\/\/doi.org\/10.1093\/bioinformatics\/btl567","journal-title":"Bioinformatics"},{"key":"3118_CR20","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s10555-015-9586-9","volume":"34","author":"IJ Fidler","year":"2015","unstructured":"Fidler IJ, Kripke ML (2015) The challenge of targeting metastasis. Cancer Metastasis Rev 34:635\u2013641. https:\/\/doi.org\/10.1007\/s10555-015-9586-9","journal-title":"Cancer Metastasis Rev"},{"key":"3118_CR21","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/nature15748","volume":"527","author":"KR Fischer","year":"2015","unstructured":"Fischer KR, Durrans A, Lee S et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472\u2013476. https:\/\/doi.org\/10.1038\/nature15748","journal-title":"Nature"},{"key":"3118_CR22","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.lungcan.2017.10.006","volume":"114","author":"V Foy","year":"2017","unstructured":"Foy V, Schenk MW, Baker K et al (2017) Targeting DNA damage in SCLC. Lung cancer 114:12\u201322. https:\/\/doi.org\/10.1016\/j.lungcan.2017.10.006","journal-title":"Lung cancer"},{"key":"3118_CR23","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1101\/gad.190678.112","volume":"26","author":"WA Freed-Pastor","year":"2012","unstructured":"Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268\u20131286. https:\/\/doi.org\/10.1101\/gad.190678.112","journal-title":"Genes Dev"},{"key":"3118_CR24","doi-asserted-by":"publisher","first-page":"101887","DOI":"10.1016\/j.ctrv.2019.08.003","volume":"79","author":"F Gelsomino","year":"2019","unstructured":"Gelsomino F, Lamberti G, Parisi C et al (2019) The evolving landscape of immunotherapy in small-cell lung cancer: a focus on predictive biomarkers. Cancer Treat Rev 79:101887. https:\/\/doi.org\/10.1016\/j.ctrv.2019.08.003","journal-title":"Cancer Treat Rev"},{"key":"3118_CR25","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1038\/s41467-018-03096-0","volume":"9","author":"A G\u00f6der","year":"2018","unstructured":"G\u00f6der A, Emmerich C, Nikolova T et al (2018) HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130. Nat Commun 9:764. https:\/\/doi.org\/10.1038\/s41467-018-03096-0","journal-title":"Nat Commun"},{"key":"3118_CR26","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10080250","author":"V Gottifredi","year":"2018","unstructured":"Gottifredi V, Wiesm\u00fcller L (2018) The tip of an iceberg: replication-associated functions of the tumor suppressor p53. Cancers. https:\/\/doi.org\/10.3390\/cancers10080250","journal-title":"Cancers"},{"key":"3118_CR27","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1016\/j.juro.2015.01.079","volume":"194","author":"T Haber","year":"2015","unstructured":"Haber T, J\u00f6ckel E, Roos FC et al (2015) Bone metastasis in renal cell carcinoma is preprogrammed in the primary tumor and caused by AKT and integrin alpha5 signaling. J Urol 194:539\u2013546. https:\/\/doi.org\/10.1016\/j.juro.2015.01.079","journal-title":"J Urol"},{"key":"3118_CR28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112767","author":"Y Hao","year":"2019","unstructured":"Hao Y, Baker D, Ten Dijke P (2019) TGF-beta-mediated epithelial-mesenchymal transition and cancer metastasis. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms20112767","journal-title":"Int J Mol Sci"},{"key":"3118_CR29","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aao5617","author":"C Jenkins","year":"2018","unstructured":"Jenkins C, Luty SB, Maxson JE et al (2018) Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia. Sci Signal. https:\/\/doi.org\/10.1126\/scisignal.aao5617","journal-title":"Sci Signal"},{"key":"3118_CR30","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.1111\/j.1582-4934.2008.00436.x","volume":"13","author":"J Jones","year":"2009","unstructured":"Jones J, Juengel E, Mickuckyte A et al (2009a) The histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo. J Cell Mol Med 13:2376\u20132385. https:\/\/doi.org\/10.1111\/j.1582-4934.2008.00436.x","journal-title":"J Cell Mol Med"},{"key":"3118_CR31","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1111\/j.1582-4934.2008.00603.x","volume":"13","author":"J Jones","year":"2009","unstructured":"Jones J, Juengel E, Mickuckyte A et al (2009b) Valproic acid blocks adhesion of renal cell carcinoma cells to endothelium and extracellular matrix. J Cell Mol Med 13:2342\u20132352. https:\/\/doi.org\/10.1111\/j.1582-4934.2008.00603.x","journal-title":"J Cell Mol Med"},{"key":"3118_CR32","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/1476-4598-13-152","volume":"13","author":"E Juengel","year":"2014","unstructured":"Juengel E, Nowaz S, Makarevi J et al (2014) HDAC-inhibition counteracts everolimus resistance in renal cell carcinoma in vitro by diminishing cdk2 and cyclin A. Mol Cancer 13:152. https:\/\/doi.org\/10.1186\/1476-4598-13-152","journal-title":"Mol Cancer"},{"key":"3118_CR33","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1007\/s00204-018-2229-5","volume":"92","author":"N Kiweler","year":"2018","unstructured":"Kiweler N, Brill B, Wirth M et al (2018) The histone deacetylases HDAC1 and HDAC2 are required for the growth and survival of renal carcinoma cells. Arch Toxicol 92:2227\u20132243. https:\/\/doi.org\/10.1007\/s00204-018-2229-5","journal-title":"Arch Toxicol"},{"key":"3118_CR34","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1016\/j.celrep.2016.10.036","volume":"17","author":"I Klusmann","year":"2016","unstructured":"Klusmann I, Rodewald S, M\u00fcller L et al (2016) p53 activity results in DNA replication fork processivity. Cell Rep 17:1845\u20131857. https:\/\/doi.org\/10.1016\/j.celrep.2016.10.036","journal-title":"Cell Rep"},{"key":"3118_CR35","doi-asserted-by":"publisher","first-page":"135","DOI":"10.3390\/cells4020135","volume":"4","author":"E Koeneke","year":"2015","unstructured":"Koeneke E, Witt O, Oehme I (2015) HDAC family members intertwined in the regulation of autophagy: a druggable vulnerability in aggressive tumor entities. Cells 4:135\u2013168. https:\/\/doi.org\/10.3390\/cells4020135","journal-title":"Cells"},{"issue":"4","key":"3118_CR36","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1101\/gad.364306","volume":"20","author":"OH Kr\u00e4mer","year":"2006","unstructured":"Kr\u00e4mer OH, Baus D, Knauer SK, Stein S, J\u00e4ger E, Stauber RH, Grez M, Pfitzner E, Heinzel T (2006) Acetylation of Stat1 modulates NF-kappaB activity. Genes Dev 20(4):473\u2013485","journal-title":"Genes Dev"},{"key":"3118_CR37","doi-asserted-by":"publisher","first-page":"3067","DOI":"10.1158\/0008-5472.CAN-15-2680","volume":"76","author":"A Krumm","year":"2016","unstructured":"Krumm A, Barckhausen C, Kucuk P et al (2016) Enhanced histone deacetylase activity in malignant melanoma provokes RAD51 and FANCD2-triggered drug resistance. Cancer Res 76:3067\u20133077. https:\/\/doi.org\/10.1158\/0008-5472.CAN-15-2680","journal-title":"Cancer Res"},{"key":"3118_CR38","doi-asserted-by":"publisher","first-page":"e27820","DOI":"10.1002\/pbc.27820","volume":"66","author":"RT Kurmasheva","year":"2019","unstructured":"Kurmasheva RT, Bandyopadhyay A, Favours E et al (2019) Evaluation of entinostat alone and in combination with standard-of-care cytotoxic agents against rhabdomyosarcoma xenograft models. Pediatr Blood Cancer 66:e27820. https:\/\/doi.org\/10.1002\/pbc.27820","journal-title":"Pediatr Blood Cancer"},{"key":"3118_CR39","doi-asserted-by":"publisher","first-page":"e101801","DOI":"10.15252\/embj.2019101801","volume":"38","author":"MC Lanz","year":"2019","unstructured":"Lanz MC, Dibitetto D, Smolka MB (2019) DNA damage kinase signaling: checkpoint and repair at 30 years. EMBO J 38:e101801. https:\/\/doi.org\/10.15252\/embj.2019101801","journal-title":"EMBO J"},{"key":"3118_CR40","doi-asserted-by":"publisher","first-page":"40622","DOI":"10.18632\/oncotarget.5872","volume":"6","author":"X Lei","year":"2015","unstructured":"Lei X, Li YF, Chen GD et al (2015) Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma. Oncotarget 6:40622\u201340641. https:\/\/doi.org\/10.18632\/oncotarget.5872","journal-title":"Oncotarget"},{"key":"3118_CR41","doi-asserted-by":"publisher","first-page":"4162","DOI":"10.1038\/onc.2014.350","volume":"34","author":"K Mahajan","year":"2015","unstructured":"Mahajan K, Mahajan NP (2015) ACK1\/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene 34:4162\u20134167. https:\/\/doi.org\/10.1038\/onc.2014.350","journal-title":"Oncogene"},{"key":"3118_CR42","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1038\/s41598-018-20172-z","volume":"8","author":"NP Mahajan","year":"2018","unstructured":"Mahajan NP, Coppola D, Kim J et al (2018) Blockade of ACK1\/TNK2 to squelch the survival of prostate cancer stem-like cells. Sci Rep 8:1954. https:\/\/doi.org\/10.1038\/s41598-018-20172-z","journal-title":"Sci Rep"},{"key":"3118_CR43","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1007\/s00432-016-2229-x","volume":"142","author":"N Mahendrarajah","year":"2016","unstructured":"Mahendrarajah N, Paulus R, Kr\u00e4mer OH (2016) Histone deacetylase inhibitors induce proteolysis of activated CDC42-associated kinase-1 in leukemic cells. J Cancer Res Clin Oncol 142:2263\u20132273. https:\/\/doi.org\/10.1007\/s00432-016-2229-x","journal-title":"J Cancer Res Clin Oncol"},{"key":"3118_CR44","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.cellsig.2017.07.014","volume":"39","author":"N Mahendrarajah","year":"2017","unstructured":"Mahendrarajah N, Borisova ME, Reichardt S et al (2017) HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3. Cell Signal 39:9\u201317. https:\/\/doi.org\/10.1016\/j.cellsig.2017.07.014","journal-title":"Cell Signal"},{"key":"3118_CR45","doi-asserted-by":"publisher","first-page":"6190","DOI":"10.3892\/mmr.2017.7394","volume":"16","author":"S Mao","year":"2017","unstructured":"Mao S, Lu G, Lan X et al (2017) Valproic acid inhibits epithelial\u2013mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression. Mol Med Rep 16:6190\u20136199. https:\/\/doi.org\/10.3892\/mmr.2017.7394","journal-title":"Mol Med Rep"},{"key":"3118_CR46","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.cytogfr.2017.05.006","volume":"37","author":"S Mertsch","year":"2017","unstructured":"Mertsch S, Kr\u00e4mer OH (2017) The interplay between histone deacetylases and rho kinases is important for cancer and neurodegeneration. Cytokine Growth Factor Rev 37:29\u201345. https:\/\/doi.org\/10.1016\/j.cytogfr.2017.05.006","journal-title":"Cytokine Growth Factor Rev"},{"key":"3118_CR47","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1111\/pin.12433","volume":"66","author":"S Mikami","year":"2016","unstructured":"Mikami S, Oya M, Mizuno R et al (2016) Recent advances in renal cell carcinoma from a pathological point of view. Pathol Int 66:481\u2013490. https:\/\/doi.org\/10.1111\/pin.12433","journal-title":"Pathol Int"},{"key":"3118_CR48","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/nsmb.1899","volume":"17","author":"KM Miller","year":"2010","unstructured":"Miller KM, Tjeertes JV, Coates J et al (2010) Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 17:1144\u20131151. https:\/\/doi.org\/10.1038\/nsmb.1899","journal-title":"Nat Struct Mol Biol"},{"key":"3118_CR49","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/s0090-4295(02)02553-0","volume":"61","author":"A Miyajima","year":"2003","unstructured":"Miyajima A, Asano T, Seta K et al (2003) Loss of expression of transforming growth factor-beta receptor as a prognostic factor in patients with renal cell carcinoma. Urology 61:1072\u20131077. https:\/\/doi.org\/10.1016\/s0090-4295(02)02553-0","journal-title":"Urology"},{"key":"3118_CR50","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1158\/2326-6066.CIR-16-0114","volume":"5","author":"SI Mosely","year":"2017","unstructured":"Mosely SI, Prime JE, Sainson RC et al (2017) Rational selection of syngeneic preclinical tumor models for immunotherapeutic drug discovery. Cancer Immunol Res 5:29\u201341. https:\/\/doi.org\/10.1158\/2326-6066.CIR-16-0114","journal-title":"Cancer Immunol Res"},{"key":"3118_CR51","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20102415","author":"M Mrakovcic","year":"2019","unstructured":"Mrakovcic M, Kleinheinz J, Fr\u00f6hlich LF (2019) p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms20102415","journal-title":"Int J Mol Sci"},{"key":"3118_CR52","doi-asserted-by":"publisher","first-page":"210","DOI":"10.2174\/156800910791054149","volume":"10","author":"S M\u00fcller","year":"2010","unstructured":"M\u00fcller S, Kr\u00e4mer OH (2010) Inhibitors of HDACs\u2013effective drugs against cancer? Curr Cancer Drug Targets 10:210\u2013228","journal-title":"Curr Cancer Drug Targets"},{"key":"3118_CR53","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1200\/JCO.2006.08.6165","volume":"25","author":"P M\u00fcnster","year":"2007","unstructured":"M\u00fcnster P, Marchion D, Bicaku E et al (2007) Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J Clin Oncol 25:1979\u20131985. https:\/\/doi.org\/10.1200\/JCO.2006.08.6165","journal-title":"J Clin Oncol"},{"key":"3118_CR54","doi-asserted-by":"publisher","first-page":"1234850","DOI":"10.1126\/science.1234850","volume":"342","author":"MA Nieto","year":"2013","unstructured":"Nieto MA (2013) Epithelial plasticity: a common theme in embryonic and cancer cells. Science 342:1234850. https:\/\/doi.org\/10.1126\/science.1234850","journal-title":"Science"},{"key":"3118_CR55","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.tips.2017.05.009","volume":"38","author":"T Nikolova","year":"2017","unstructured":"Nikolova T, Kiweler N, Kr\u00e4mer OH (2017) Interstrand crosslink repair as a target for HDAC inhibition. Trends Pharmacol Sci 38:822\u2013836. https:\/\/doi.org\/10.1016\/j.tips.2017.05.009","journal-title":"Trends Pharmacol Sci"},{"key":"3118_CR56","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1007\/s00204-016-1878-5","volume":"91","author":"K Noack","year":"2017","unstructured":"Noack K, Mahendrarajah N, Hennig D et al (2017) Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells. Arch Toxicol 91:2191\u20132208. https:\/\/doi.org\/10.1007\/s00204-016-1878-5","journal-title":"Arch Toxicol"},{"key":"3118_CR57","doi-asserted-by":"publisher","first-page":"36734","DOI":"10.1074\/jbc.M101287200","volume":"276","author":"CJ Phiel","year":"2001","unstructured":"Phiel CJ, Zhang F, Huang EY et al (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734\u201336741. https:\/\/doi.org\/10.1074\/jbc.M101287200","journal-title":"J Biol Chem"},{"key":"3118_CR58","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s40291-016-0192-5","volume":"20","author":"F Piva","year":"2016","unstructured":"Piva F, Giulietti M, Santoni M et al (2016) Epithelial to mesenchymal transition in renal cell carcinoma: implications for cancer therapy. Mol Diagn Therapy 20:111\u2013117. https:\/\/doi.org\/10.1007\/s40291-016-0192-5","journal-title":"Mol Diagn Therapy"},{"key":"3118_CR59","doi-asserted-by":"publisher","first-page":"5858","DOI":"10.1074\/jbc.273.10.5858","volume":"273","author":"EP Rogakou","year":"1998","unstructured":"Rogakou EP, Pilch DR, Orr AH et al (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858\u20135868. https:\/\/doi.org\/10.1074\/jbc.273.10.5858","journal-title":"J Biol Chem"},{"key":"3118_CR60","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.cellsig.2016.11.002","volume":"29","author":"C Sch\u00e4fer","year":"2017","unstructured":"Sch\u00e4fer C, G\u00f6der A, Beyer M et al (2017) Class I histone deacetylases regulate p53\/NF-kappaB crosstalk in cancer cells. Cell Signal 29:218\u2013225. https:\/\/doi.org\/10.1016\/j.cellsig.2016.11.002","journal-title":"Cell Signal"},{"key":"3118_CR61","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1038\/onc.2010.46","volume":"29","author":"G Schneider","year":"2010","unstructured":"Schneider G, Henrich A, Greiner G et al (2010) Cross talk between stimulated NF-kappaB and the tumor suppressor p53. Oncogene 29:2795\u20132806. https:\/\/doi.org\/10.1038\/onc.2010.46","journal-title":"Oncogene"},{"key":"3118_CR62","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12935-018-0555-6","volume":"18","author":"M Singla","year":"2018","unstructured":"Singla M, Kumar A, Bal A et al (2018) Epithelial to mesenchymal transition induces stem cell like phenotype in renal cell carcinoma cells. Cancer Cell Int 18:57. https:\/\/doi.org\/10.1186\/s12935-018-0555-6","journal-title":"Cancer Cell Int"},{"key":"3118_CR63","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/bjc.2013.742","volume":"110","author":"J Sonnemann","year":"2014","unstructured":"Sonnemann J, Marx C, Becker S et al (2014) p53-dependent and p53-independent anticancer effects of different histone deacetylase inhibitors. Br J Cancer 110:656\u2013667. https:\/\/doi.org\/10.1038\/bjc.2013.742","journal-title":"Br J Cancer"},{"key":"3118_CR64","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1038\/onc.2016.344","volume":"36","author":"N Stojanovic","year":"2017","unstructured":"Stojanovic N, Hassan Z, Wirth M et al (2017) HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. Oncogene 36:1804\u20131815. https:\/\/doi.org\/10.1038\/onc.2016.344","journal-title":"Oncogene"},{"key":"3118_CR65","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.18632\/oncotarget.26682","volume":"10","author":"S Tretbar","year":"2019","unstructured":"Tretbar S, Krausbeck P, M\u00fcller A et al (2019) TGF-beta inducible epithelial-to-mesenchymal transition in renal cell carcinoma. Oncotarget 10:1507\u20131524. https:\/\/doi.org\/10.18632\/oncotarget.26682","journal-title":"Oncotarget"},{"key":"3118_CR66","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.tips.2017.11.008","volume":"39","author":"I Vancurova","year":"2018","unstructured":"Vancurova I, Uddin MM, Zou Y, Vancura A (2018) Combination therapies targeting HDAC and IKK in solid tumors. Trends Pharmacol Sci 39:295\u2013306. https:\/\/doi.org\/10.1016\/j.tips.2017.11.008","journal-title":"Trends Pharmacol Sci"},{"key":"3118_CR67","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.dnarep.2011.10.014","volume":"11","author":"H Wang","year":"2012","unstructured":"Wang H, Zhou W, Zheng Z et al (2012) The HDAC inhibitor depsipeptide transactivates the p53\/p21 pathway by inducing DNA damage. DNA Repair 11:146\u2013156. https:\/\/doi.org\/10.1016\/j.dnarep.2011.10.014","journal-title":"DNA Repair"},{"key":"3118_CR68","doi-asserted-by":"publisher","first-page":"102361","DOI":"10.18632\/oncotarget.21971","volume":"8","author":"Z Wang","year":"2017","unstructured":"Wang Z, Peng S, Jiang N et al (2017) Prognostic and clinicopathological value of p53 expression in renal cell carcinoma: a meta-analysis. Oncotarget 8:102361\u2013102370. https:\/\/doi.org\/10.18632\/oncotarget.21971","journal-title":"Oncotarget"},{"key":"3118_CR69","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1186\/s12885-018-4344-3","volume":"18","author":"M Wei","year":"2018","unstructured":"Wei M, Mao S, Lu G et al (2018) Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal. BMC Cancer 18:434. https:\/\/doi.org\/10.1186\/s12885-018-4344-3","journal-title":"BMC Cancer"},{"key":"3118_CR70","doi-asserted-by":"publisher","first-page":"e68915","DOI":"10.1371\/journal.pone.0068915","volume":"8","author":"CE Wells","year":"2013","unstructured":"Wells CE, Bhaskara S, Stengel KR et al (2013) Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS ONE 8:e68915. https:\/\/doi.org\/10.1371\/journal.pone.0068915","journal-title":"PLoS ONE"},{"key":"3118_CR71","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1002\/path.4515","volume":"236","author":"SH Xu","year":"2015","unstructured":"Xu SH, Huang JZ, Xu ML et al (2015) ACK1 promotes gastric cancer epithelial-mesenchymal transition and metastasis through AKT-POU2F1-ECD signalling. J Pathol 236:175\u2013185. https:\/\/doi.org\/10.1002\/path.4515","journal-title":"J Pathol"},{"key":"3118_CR72","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1038\/nature22816","volume":"547","author":"X Ye","year":"2017","unstructured":"Ye X, Brabletz T, Kang Y et al (2017) Upholding a role for EMT in breast cancer metastasis. Nature 547:E1\u2013E3. https:\/\/doi.org\/10.1038\/nature22816","journal-title":"Nature"},{"key":"3118_CR73","doi-asserted-by":"publisher","first-page":"C1207","DOI":"10.1152\/ajpcell.00253.2012","volume":"303","author":"YC Yeh","year":"2012","unstructured":"Yeh YC, Lin HH, Tang MJ (2012) A tale of two collagen receptors, integrin beta1 and discoidin domain receptor 1, in epithelial cell differentiation American journal of physiology. Cell Physiol 303:C1207\u20131217. https:\/\/doi.org\/10.1152\/ajpcell.00253.2012","journal-title":"Cell Physiol"},{"issue":"1","key":"3118_CR74","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1681\/ASN.2005111187","volume":"18","author":"M Yoshikawa","year":"2007","unstructured":"Yoshikawa M, Hishikawa K, Marumo T, Fujita T (2007) Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. J Am Soc Nephrol 18(1):58\u201365","journal-title":"J Am Soc Nephrol"},{"key":"3118_CR75","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1172\/JCI36183","volume":"119","author":"M Zeisberg","year":"2009","unstructured":"Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Investig 119:1429\u20131437. https:\/\/doi.org\/10.1172\/JCI36183","journal-title":"J Clin Investig"},{"key":"3118_CR76","doi-asserted-by":"crossref","unstructured":"Zeitouni B, Tschuch C, Davis JM et al (2017) Abstract 1840: whole-exome somatic mutation analysis of mouse cancer models and implications for preclinical immunomodulatory drug development. Cancer Res 77(13 Suppl):Abstract nr 1840. doi: 10.1158\/1538-7445.AM2017-1840","DOI":"10.1158\/1538-7445.AM2017-1840"},{"key":"3118_CR77","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nature16064","volume":"527","author":"X Zheng","year":"2015","unstructured":"Zheng X, Carstens JL, Kim J et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525\u2013530. https:\/\/doi.org\/10.1038\/nature16064","journal-title":"Nature"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-019-03118-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00432-019-03118-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-019-03118-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T20:56:23Z","timestamp":1610484983000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00432-019-03118-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,13]]},"references-count":77,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["3118"],"URL":"https:\/\/doi.org\/10.1007\/s00432-019-03118-4","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"value":"0171-5216","type":"print"},{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,13]]},"assertion":[{"value":"9 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}