{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T02:08:26Z","timestamp":1789610906219,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T00:00:00Z","timestamp":1727827200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Despite significant advances in the treatment of cutaneous melanoma (hereafter\u00a0melanoma), the prognosis remains less favorable due to therapeutic resistance, which is presumably linked to epigenetic dysregulation. We hypothesized that the histone lysine demethylase KDM4B could play a pivotal role in controlling therapy\u2010resistant melanoma. To validate our hypothesis, we retrieved RNA sequencing data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA)\u00a0program and observed upregulation of <jats:italic>KDM4B<\/jats:italic> in both primary and metastatic melanoma, which was associated with poor survival. To explore its role, we used murine B16, human SK\u2010MEL\u20105, and G\u2010361 melanoma cells as in vitro models of melanoma. We found that KDM4B inhibition using NCGC00244536 increased global levels of H3K9me3 and downregulated the expressions of cell cycle progression\u2013related genes <jats:italic>Cdk1<\/jats:italic>, <jats:italic>Cdk4<\/jats:italic>, <jats:italic>Ccnb1<\/jats:italic>, and <jats:italic>Ccnd1<\/jats:italic>. Moreover, genetic ablation of <jats:italic>KDM4B<\/jats:italic> or its chemical inhibition using NCGC00244536 reduced p53 production by upregulating MDM2, which enhances the proteolytic degradation of p53. Interestingly, despite the reduction of p53, these interventions augmented apoptosis and senescence\u2010induced cell death by activating pathways downstream of p53, as evidenced by reduced levels of pro\u2010survival Bcl\u20102 and Bcl\u2010xL proteins and increased production of pro\u2010apoptotic cleaved caspase\u20103, caspase\u20107, <jats:italic>Bax<\/jats:italic>, and the senescence inducer <jats:italic>Cdkn1a<\/jats:italic>. Compared to the FDA\u2010approved anti\u2010melanoma agent dacarbazine, NCGC00244536 exhibited more pronounced cytotoxic and antiproliferative effects in melanoma cells. Importantly, NCGC00244536 demonstrated minimal cytotoxicity to low <jats:italic>Kdm4b<\/jats:italic>\u2010expressing mouse embryonic fibroblasts. In conclusion, our findings suggest that KDM4B inhibition can override the antitumor effect of p53, and potentially serve as a therapeutic strategy for melanoma.<\/jats:p>","DOI":"10.1002\/jcb.30643","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T04:20:36Z","timestamp":1727929236000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["KDM4B Histone Demethylase Inhibition Attenuates Tumorigenicity of Malignant Melanoma Cells by Overriding the p53\u2010Mediated Tumor Suppressor Pathway"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6491-347X","authenticated-orcid":false,"given":"Arif Ul","family":"Hasan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine Iwate Medical University Iwate 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