{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:08:08Z","timestamp":1790770088278,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mantle cell lymphoma (MCL) is a rare subtype of non\u2010Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1\/2), OR\u2010S1 (a close analog of the clinical\u2010stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib\u2010resistant MCL patient\u2013derived xenograft (PDX) mouse model, OR\u2010S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2\u2010specific inhibitor GSK126, OR\u2010S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR\u2010S1\u2013sensitive or insensitive MCL cell lines and showed that OR\u2010S1 treatment modulated B\u2010cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1\/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1\/2 may be a potential novel target for the treatment of aggressive ibrutinib\u2010resistant MCL via CDKN1C\u2010mediated cell cycle arrest.<\/jats:p>","DOI":"10.1111\/cas.14905","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T23:05:47Z","timestamp":1617231947000},"page":"2314-2324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["CDKN1C\u2010mediated growth inhibition by an EZH1\/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib"],"prefix":"10.1111","volume":"112","author":[{"given":"Yuki","family":"Kagiyama","sequence":"first","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Fujita","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Shima","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutsune","family":"Yamagata","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuo","family":"Katsumoto","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Honma","sequence":"additional","affiliation":[{"name":"Oncology Research Laboratories Daiichi Sankyo Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9452-0685","authenticated-orcid":false,"given":"Nobuaki","family":"Adachi","sequence":"additional","affiliation":[{"name":"Oncology Research Laboratories Daiichi Sankyo Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazushi","family":"Araki","sequence":"additional","affiliation":[{"name":"Oncology Research Laboratories Daiichi Sankyo Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Kato","sequence":"additional","affiliation":[{"name":"Discovery Science and Technology Department Daiichi Sankyo RD Novare Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Inaki","sequence":"additional","affiliation":[{"name":"Discovery Science and Technology Department Daiichi Sankyo RD Novare Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimasa","family":"Ono","sequence":"additional","affiliation":[{"name":"Discovery Science and Technology Department Daiichi Sankyo RD Novare Co., Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suguru","family":"Fukuhara","sequence":"additional","affiliation":[{"name":"Department of Haematology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukio","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Haematology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensei","family":"Tobinai","sequence":"additional","affiliation":[{"name":"Department of Haematology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8409-0407","authenticated-orcid":false,"given":"Issay","family":"Kitabayashi","sequence":"additional","affiliation":[{"name":"Division of Haematological Malignancy National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23608"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2230"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61272"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1004594107"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-386417"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12974"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70311-0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306220"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-10-673145"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0098"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3517"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.08.001"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-09-3585"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni876"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.04.011"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-280149"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.518"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11606"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1084"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1210371110"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303800110"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.09.017"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.02641.x"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.12.3896"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.26546"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2016.1164375"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-147645"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1850"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-634428"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.09.013"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.300"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13326"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4036"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005011"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602079113"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.02.052"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70626"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4293"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.12.1501"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-804344"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-438937"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-04-639542"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14905","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.14905","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.14905","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T15:44:01Z","timestamp":1692546241000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.14905"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":42,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1111\/cas.14905"],"URL":"https:\/\/doi.org\/10.1111\/cas.14905","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]},"assertion":[{"value":"2020-11-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}