{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T15:11:20Z","timestamp":1780931480240,"version":"3.54.1"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K17393"],"award-info":[{"award-number":["20K17393"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Histone deacetylase inhibitors, such as vorinostat, show promise as treatment for T\u2010cell lymphomas including cutaneous T\u2010cell lymphoma. However, the emergence of resistance ultimately leads to disease relapse. To elucidate the underlying mechanisms and identify potential countermeasures, we established histone deacetylase inhibitor\u2010resistant cutaneous T\u2010cell lymphoma cell lines by prolonged exposure to vorinostat. We then comprehensively profiled gene expression in these cell lines by using microarrays and in silico analytical approaches. We identified 83 genes that were significantly upregulated in the resistant cell lines. Subsequent enrichment analyses using ChIP\u2010Atlas and Enrichr revealed that these genes are regulated by particular transcription factors, including RELA\/p65, GATA3, and EP300, of which RELA (p65) exhibited the highest composite score. RELA is a key subunit of the NF\u2010\u03baB complex, which is involved in inflammation, cell survival, and proliferation. We demonstrated marked upregulation and nuclear enrichment of p65 and pronounced NF\u2010\u03baB pathway activation in the histone deacetylase inhibitor\u2010resistant cells. The mechanism involved acetylation\u2010mediated inhibition of p65 ubiquitination, which resulted in protein stabilization and enhanced transcriptional activity. Histone deacetylase inhibitor\u2010resistant cell lines displayed heightened sensitivity to inhibition of the NF\u2010\u03baB pathway by bortezomib and dimethyl fumarate. These findings implicate aberrant NF\u2010\u03baB activation as a central driver of the emergence of histone deacetylase inhibitor resistance in cutaneous T\u2010cell lymphoma. Ultimately, our results provide a strong rationale for exploring NF\u2010\u03baB inhibition as a therapeutic strategy to restore or enhance the efficacy of histone deacetylase inhibitor\u2010based therapies, overcome histone deacetylase inhibitor resistance, and improve outcomes for patients with cutaneous T\u2010cell lymphoma.<\/jats:p>","DOI":"10.1111\/cas.70251","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T14:14:14Z","timestamp":1763129654000},"page":"407-417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>NF<\/scp>\n                    \u2010\n                    <scp>\u03baB<\/scp>\n                    Is a Potential Therapeutic Target for Histone Deacetylase Inhibitor\u2010Resistant Cutaneous T\u2010Cell Lymphoma"],"prefix":"10.1111","volume":"117","author":[{"given":"Yuto","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Life Science, Graduate School of Engineering Science Akita University  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3218-2446","authenticated-orcid":false,"given":"Akihiro","family":"Kitadate","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Iwama","sequence":"additional","affiliation":[{"name":"Department of Life Science, Graduate School of Engineering Science Akita University  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Kuroki","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3780-2993","authenticated-orcid":false,"given":"Sho","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Tagawa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Wakui","sequence":"additional","affiliation":[{"name":"Department of Life Science, Graduate School of Engineering Science Akita University  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Hikida","sequence":"additional","affiliation":[{"name":"Department of Life Science, Graduate School of Engineering Science Akita University  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-3787","authenticated-orcid":false,"given":"Naoto","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nephrology, and Rheumatology Akita University Graduate School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25577"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17117"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-154609"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-018-3275-z"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12102856"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004710"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30379-6"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-018-0678-x"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2850"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867324666170207142740"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2010.08301.x"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.22674"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon.12.173"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00092"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.4223"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.2782"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.280996"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15431"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-06-025999"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.10.2434"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.180316197"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307708100"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1272"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.939"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.435"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-09-527739"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15296"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6916"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13810"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002297"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3442"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201846255"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.383380"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2014.09.009"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00120"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-19-0087"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2021.109450"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-11-22"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062374"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf660"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.18.7966-7975.2005"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.20.7065-7077.2001"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209572200"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00862-4"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-011-1766-x"},{"key":"e_1_2_12_48_1","first-page":"4916","article-title":"FK228 (Depsipeptide) as a Natural Prodrug That Inhibits Class I Histone Deacetylases","volume":"62","author":"Furumai R.","year":"2002","journal-title":"Cancer Research"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-005-0182-5"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2009.01239.x"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022018669"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70251","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.70251","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70251","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T13:27:27Z","timestamp":1769952447000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1111\/cas.70251"],"URL":"https:\/\/doi.org\/10.1111\/cas.70251","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,14]]},"assertion":[{"value":"2025-06-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}