{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T07:59:25Z","timestamp":1774511965369,"version":"3.50.1"},"reference-count":67,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,10]],"date-time":"2020-10-10T00:00:00Z","timestamp":1602288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MECONC\/ 29043\/2017"],"award-info":[{"award-number":["PTDC\/MECONC\/ 29043\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/132751\/2017"],"award-info":[{"award-number":["SFRH\/BD\/132751\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-29043"],"award-info":[{"award-number":["POCI-01-0145-FEDER-29043"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["POCI-01-0145-FEDER-29030"],"award-info":[{"award-number":["POCI-01-0145-FEDER-29030"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Novel treatment options are needed for testicular germ cell tumor (TGCT) patients, particularly important for those showing or developing cisplatin resistance, the major cause of cancer-related deaths. As TGCTs pathobiology is highly related to epigenetic (de)regulation, epidrugs are potentially effective therapies. Hence, we sought to explore, for the first time, the effect of the two most recently FDA-approved HDAC inhibitors (HDACis), belinostat and panobinostat, in (T)GCT cell lines including those resistant to cisplatin. In silico results were validated in 261 patient samples and differential expression of HDACs was also observed across cell lines. Belinostat and panobinostat reduced cell viability in both cisplatin-sensitive cells (NCCIT-P, 2102Ep-P, and NT2-P) and, importantly, also in matched cisplatin-resistant subclones (NCCIT-R, 2102Ep-R, and NT2-R), with IC50s in the low nanomolar range for all cell lines. Treatment of NCCIT-R with both drugs increased acetylation, induced cell cycle arrest, reduced proliferation, decreased Ki67 index, and increased p21, while increasing cell death by apoptosis, with upregulation of cleaved caspase 3. These findings support the effectiveness of HDACis for treating TGCT patients in general, including those developing cisplatin resistance. Future studies should explore them as single or combination agents.<\/jats:p>","DOI":"10.3390\/cancers12102903","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T21:42:21Z","timestamp":1602798141000},"page":"2903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Efficacy of HDAC Inhibitors Belinostat and Panobinostat against Cisplatin-Sensitive and Cisplatin-Resistant Testicular Germ Cell Tumors"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Lobo","sequence":"first","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"},{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}]},{"given":"Catarina","family":"Guimar\u00e3es-Teixeira","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-6807","authenticated-orcid":false,"given":"Daniela","family":"Barros-Silva","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4231-5532","authenticated-orcid":false,"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"given":"V\u00e2nia","family":"Camilo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"given":"Rita","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"given":"Mariana","family":"Cantante","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"given":"Isaac","family":"Braga","sequence":"additional","affiliation":[{"name":"Department of Urology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"given":"Joaquina","family":"Maur\u00edcio","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5578-3418","authenticated-orcid":false,"given":"Christoph","family":"Oing","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistra\u00dfe 52, 20246 Hamburg, Germany"},{"name":"Laboratory of Radiation Biology and Experimental Radiation Oncology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3700-3577","authenticated-orcid":false,"given":"Friedemann","family":"Honecker","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistra\u00dfe 52, 20246 Hamburg, Germany"},{"name":"Tumour and Breast Center ZeTuP St. Gallen, Rorschacher Strasse 150, 9006 St. Gallen, Switzerland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4483-845X","authenticated-orcid":false,"given":"Daniel","family":"Nettersheim","sequence":"additional","affiliation":[{"name":"Department of Urology, Urological Research Lab, Translational UroOncology, University Hospital D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-1911","authenticated-orcid":false,"given":"Leendert H. J.","family":"Looijenga","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[{"name":"Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) &amp; Porto Comprehensive Cancer Center (P.CCC), R. Dr. Ant\u00f3nio Bernardino de Almeida, 4200-072 Porto, Portugal"},{"name":"Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lobo, J., Gillis, A.J.M., Jeronimo, C., Henrique, R., and Looijenga, L.H.J. (2019). Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020258"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41568-019-0178-9","article-title":"Human germ cell tumours from a developmental perspective","volume":"19","author":"Oosterhuis","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.humpath.2018.07.016","article-title":"Testicular germ cell tumors: Revisiting a series in light of the new WHO classification and AJCC staging systems, focusing on challenges for pathologists","volume":"82","author":"Lobo","year":"2018","journal-title":"Hum. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1093\/annonc\/mdy217","article-title":"ESMO Consensus Conference on testicular germ cell cancer: Diagnosis, treatment and follow-up","volume":"29","author":"Honecker","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF00184714","article-title":"The impact of the \u201ccisplatin era\u201d of treatment on survival in testicular cancer","volume":"9","author":"Moul","year":"1991","journal-title":"World J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41572-018-0029-0","article-title":"Testicular cancer","volume":"4","author":"Cheng","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1093\/annonc\/mdx360","article-title":"Long-term toxicity of cisplatin in germ-cell tumor survivors","volume":"28","author":"Chovanec","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/14737140.2018.1450630","article-title":"Therapeutic approaches for refractory germ cell cancer","volume":"18","author":"Oing","year":"2018","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s00345-016-1898-z","article-title":"Platinum-refractory germ cell tumors: An update on current treatment options and developments","volume":"35","author":"Oing","year":"2017","journal-title":"World J. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1007\/s11912-018-0730-x","article-title":"Molecular Mechanisms of Cisplatin Chemoresistance and Its Circumventing in Testicular Germ Cell Tumors","volume":"20","author":"Schmidtova","year":"2018","journal-title":"Curr. Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/andr.299","article-title":"Cisplatin resistance in germ cell tumours: Models and mechanisms","volume":"3","author":"Jacobsen","year":"2015","journal-title":"Andrology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1080\/14737140.2020.1717337","article-title":"Molecular characteristics of testicular germ cell tumors: Pathogenesis and mechanisms of therapy resistance","volume":"20","author":"Chovanec","year":"2020","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1038\/s41467-020-15768-x","article-title":"Genomic landscape of platinum resistant and sensitive testicular cancers","volume":"11","author":"Loveday","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_14","first-page":"580","article-title":"Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors","volume":"2","author":"Singh","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1476-4598-3-16","article-title":"Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors","volume":"3","author":"Koul","year":"2004","journal-title":"Mol. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Singh, R., Fazal, Z., Corbet, A.K., Bikorimana, E., Rodriguez, J.C., Khan, E.M., Shahid, K., Freemantle, S.J., and Spinella, M.J. (2019). Epigenetic Remodeling through Downregulation of Polycomb Repressive Complex 2 Mediates Chemotherapy Resistance in Testicular Germ Cell Tumors. Cancers, 11.","DOI":"10.3390\/cancers11060796"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2217\/epi-2016-0081","article-title":"The epigenetics of testicular germ cell tumors: Looking for novel disease biomarkers","volume":"9","author":"Costa","year":"2017","journal-title":"Epigenomics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1002\/jcp.24394","article-title":"MicroRNA-302a sensitizes testicular embryonal carcinoma cells to cisplatin-induced cell death","volume":"228","author":"Liu","year":"2013","journal-title":"J. Cell Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/andr.12611","article-title":"Epigenetic treatment combinations to effectively target cisplatin-resistant germ cell tumors: Past, present, and future considerations","volume":"7","author":"Oing","year":"2019","journal-title":"Andrology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cardoso, A.R., Lobo, J., Miranda-Goncalves, V., Henrique, R., and Jeronimo, C. (2020). Epigenetic alterations as therapeutic targets in Testicular Germ Cell Tumours: Current and future application of \u2018epidrugs\u2019. Epigenetics, 1\u201320.","DOI":"10.1080\/15592294.2020.1805682"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1038\/bjc.2014.128","article-title":"Aza-deoxycytidine induces apoptosis or differentiation via DNMT3B and targets embryonal carcinoma cells but not their differentiated derivatives","volume":"110","author":"Wongtrakoongate","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Biswal, B.K., Beyrouthy, M.J., Hever-Jardine, M.P., Armstrong, D., Tomlinson, C.R., Christensen, B.C., Marsit, C.J., and Spinella, M.J. (2012). Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0053003"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Oing, C., Verem, I., Mansour, W.Y., Bokemeyer, C., Dyshlovoy, S., and Honecker, F. (2018). 5-Azacitidine Exerts Prolonged Pro-Apoptotic Effects and Overcomes Cisplatin-Resistance in Non-Seminomatous Germ Cell Tumor Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010021"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.18632\/oncotarget.13811","article-title":"Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine","volume":"8","author":"Albany","year":"2017","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1111\/jcmm.13059","article-title":"The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo","volume":"21","author":"Jostes","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"74931","DOI":"10.18632\/oncotarget.11647","article-title":"A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and affects the cell cycle of germ cell cancers after romidepsin treatment","volume":"7","author":"Nettersheim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1002\/gcc.20918","article-title":"The seminoma cell line TCam-2 is sensitive to HDAC inhibitor depsipeptide but tolerates various other chemotherapeutic drugs and loss of NANOG expression","volume":"50","author":"Nettersheim","year":"2011","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bakardjieva-Mihaylova, V., Skvarova Kramarzova, K., Slamova, M., Svaton, M., Rejlova, K., Zaliova, M., Dobiasova, A., Fiser, K., Stuchly, J., and Grega, M. (2019). Molecular Basis of Cisplatin Resistance in Testicular Germ Cell Tumors. Cancers, 11.","DOI":"10.3390\/cancers11091316"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/sj.bjc.6604932","article-title":"Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo","volume":"100","author":"Steele","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"967","DOI":"10.2174\/1568009618666180102103959","article-title":"Molecular Mechanisms of Resistance in Testicular Germ Cell Tumors\u2014Clinical Implications","volume":"18","author":"Kalavska","year":"2018","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11912-017-0572-y","article-title":"Current Management of Refractory Germ Cell Tumors and Future Directions","volume":"19","author":"Allen","year":"2017","journal-title":"Curr. Oncol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1007\/s10637-019-00805-4","article-title":"Phase II study of avelumab in multiple relapsed\/refractory germ cell cancer","volume":"37","author":"Mego","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00432-019-03071-2","article-title":"Treatment of refractory germ-cell tumours with single-agent cabazitaxel: A German Testicular Cancer Study Group case series","volume":"146","author":"Oing","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s00432-018-2752-z","article-title":"Everolimus in patients with multiply relapsed or cisplatin refractory germ cell tumors: Results of a phase II, single-arm, open-label multicenter trial (RADIT) of the German Testicular Cancer Study Group","volume":"145","author":"Fenner","year":"2019","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1093\/annonc\/mdx680","article-title":"Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: A Hoosier Cancer Research Network Study GU14-206","volume":"29","author":"Adra","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.eururo.2018.09.010","article-title":"An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis","volume":"75","author":"Necchi","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9360","DOI":"10.1158\/0008-5472.CAN-09-1490","article-title":"High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors","volume":"69","author":"Beyrouthy","year":"2009","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1158\/1078-0432.CCR-17-3055","article-title":"A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses","volume":"24","author":"Matei","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF00874155","article-title":"5-Azacytidine (NSC 102816) in refractory germ cell tumors. A phase II trial of the Eastern Cooperative Oncology Group","volume":"11","author":"Roth","year":"1993","journal-title":"Investig. New Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molonc.2007.01.001","article-title":"The role of histone deacetylases (HDACs) in human cancer","volume":"1","author":"Ropero","year":"2007","journal-title":"Mol. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Moreira-Silva, F., Camilo, V., Gaspar, V., Mano, J.F., Henrique, R., and Jeronimo, C. (2020). Repurposing Old Drugs into New Epigenetic Inhibitors: Promising Candidates for Cancer Treatment?. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12050410"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00418-006-0234-x","article-title":"DNMT1 and HDAC1 gene expression in impaired spermatogenesis and testicular cancer","volume":"127","author":"Omisanjo","year":"2007","journal-title":"Histochem. Cell Biol."},{"key":"ref_44","first-page":"1555","article-title":"Expression of histone deacetylases 1, 2 and 3 in histological subtypes of testicular germ cell tumours","volume":"26","author":"Fritzsche","year":"2011","journal-title":"Histol. Histopathol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lobo, J., Henrique, R., and Jeronimo, C. (2018). The Role of DNA\/Histone Modifying Enzymes and Chromatin Remodeling Complexes in Testicular Germ Cell Tumors. Cancers, 11.","DOI":"10.3390\/cancers11010006"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1128\/MCB.00631-13","article-title":"LSD1 regulates pluripotency of embryonic stem\/carcinoma cells through histone deacetylase 1-mediated deacetylation of histone H4 at lysine 16","volume":"34","author":"Yin","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4722","DOI":"10.1038\/s41598-020-61295-6","article-title":"Novel HDAC11 inhibitors suppress lung adenocarcinoma stem cell self-renewal and overcome drug resistance by suppressing Sox2","volume":"10","author":"Mohankumar","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Eini, R., Stoop, H., Gillis, A.J., Biermann, K., Dorssers, L.C., and Looijenga, L.H. (2014). Role of SOX2 in the etiology of embryonal carcinoma, based on analysis of the NCCIT and NT2 cell lines. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0083585"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/bjc.2016.187","article-title":"The cancer\/testis-antigen PRAME supports the pluripotency network and represses somatic and germ cell differentiation programs in seminomas","volume":"115","author":"Nettersheim","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/jcmm.13971","article-title":"Deciphering the molecular effects of romidepsin on germ cell tumours: DHRS2 is involved in cell cycle arrest but not apoptosis or induction of romidepsin effectors","volume":"23","author":"Nettersheim","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1177\/1078155216673229","article-title":"Romidepsin-associated cardiac toxicity and ECG changes: A case report and review of the literature","volume":"24","author":"Rivers","year":"2018","journal-title":"J. Oncol. Pharm. Pract."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1054\/bjoc.2000.1327","article-title":"P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228","volume":"83","author":"Sandor","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.4161\/cc.10.18.17190","article-title":"Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer","volume":"10","author":"Luchenko","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_54","first-page":"7291","article-title":"Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA","volume":"63","author":"Kim","year":"2003","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3892\/ijo.2015.2996","article-title":"The synergistic effects of DNA-damaging drugs cisplatin and etoposide with a histone deacetylase inhibitor valproate in high-risk neuroblastoma cells","volume":"47","author":"Groh","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_56","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_57","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3389\/fgene.2018.00427","article-title":"Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets","volume":"9","author":"Lameirinhas","year":"2018","journal-title":"Front. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1158\/0008-5472.CAN-12-2876","article-title":"Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4","volume":"73","author":"Gutekunst","year":"2013","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"26495","DOI":"10.1074\/jbc.M112.376319","article-title":"Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin","volume":"287","author":"Grande","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3624","DOI":"10.1073\/pnas.1016201108","article-title":"Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes","volume":"108","author":"Beyer","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1200\/JCO.1997.15.2.594","article-title":"International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group","volume":"15","author":"Wilkinson","year":"1997","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.2217\/epi-2018-0034","article-title":"DNA methylation profiling as a tool for testicular germ cell tumors subtyping","volume":"10","author":"Costa","year":"2018","journal-title":"Epigenomics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12967-019-1837-z","article-title":"m(6)A RNA modification and its writer\/reader VIRMA\/YTHDF3 in testicular germ cell tumors: A role in seminoma phenotype maintenance","volume":"17","author":"Lobo","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Lobo, J., Rodrigues, A., Guimaraes, R., Cantante, M., Lopes, P., Mauricio, J., Oliveira, J., Jeronimo, C., and Henrique, R. (2019). Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1\/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers. Cancers, 11.","DOI":"10.3390\/cancers11101535"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lobo, J., Gillis, A.J.M., van den Berg, A., Dorssers, L.C.J., Belge, G., Dieckmann, K.P., Roest, H.P., van der Laan, L.J.W., Gietema, J., and Hamilton, R.J. (2019). Identification and Validation Model for Informative Liquid Biopsy-Based microRNA Biomarkers: Insights from Germ Cell Tumor In Vitro, In Vivo and Patient-Derived Data. Cells, 8.","DOI":"10.3390\/cells8121637"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41416-020-0891-x","article-title":"CDK4\/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms","volume":"123","author":"Skowron","year":"2020","journal-title":"Br. J. 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