{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:24Z","timestamp":1789448544813,"version":"build-2803163510"},"reference-count":71,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 CA269685"],"award-info":[{"award-number":["R01 CA269685"]}]},{"DOI":"10.13039\/100000005","name":"DOD","doi-asserted-by":"publisher","award":["CA210457"],"award-info":[{"award-number":["CA210457"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"DOD","doi-asserted-by":"publisher","award":["CA230323"],"award-info":[{"award-number":["CA230323"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031445","name":"NJCCR","doi-asserted-by":"crossref","award":["COCR26RBG006"],"award-info":[{"award-number":["COCR26RBG006"]}],"id":[{"id":"10.13039\/100031445","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Epigenetic dysregulation is a defining feature of solid tumors. Among epigenetic regulators, the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases, comprising NSD1, NSD2, and NSD3, have emerged as critical mediators of oncogenic chromatin remodeling and transcriptional regulation. These enzymes primarily catalyze histone H3 lysine 36 (H3K36) methylation, thereby regulating chromatin accessibility, transcriptional programs, DNA damage repair, and genome stability. Aberrant expression, mutation, amplification, and chromosomal rearrangement of NSD family members have been identified across tumors, establishing them as key epigenetic drivers of malignancy. Accumulating evidence demonstrates that NSD proteins promote multiple hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, immune evasion, metabolic reprogramming, genome instability, and therapeutic resistance. Although NSD proteins share overlapping catalytic functions, each exhibit distinct biological roles and mechanisms of dysregulation in solid tumors. Advances in structural biology, medicinal chemistry, and targeted protein degradation have accelerated the development of selective NSD inhibitors, chromatin-reader antagonists, and proteolysis-targeting chimeras (PROTACs), establishing the feasibility of pharmacologically targeting NSD-dependent epigenetic pathways. In this review, we summarize the biological functions of the NSD family, discuss their oncogenic mechanisms in solid tumors, and highlight recent progress in therapeutic targeting.<\/jats:p>","DOI":"10.3390\/ijms27188115","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NSD Histone Methyltransferases in Solid Tumors: Biological Functions, Oncogenic Mechanisms and Therapeutic Targeting"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8647-9021","authenticated-orcid":false,"given":"Yan-ting Yann","family":"Zhang","sequence":"first","affiliation":[{"name":"Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"Department of Biomedical Sciences, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Plenn","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey","family":"Sun","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Basic Science Building, 301 University Boulevard, Galveston, TX 77555, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Spitz","sequence":"additional","affiliation":[{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Cooper University Hospital, 2 Cooper Plaza, Camden, NJ 08103, USA"},{"name":"Cooper University Hospital, Department of Surgery, Cooper Medical School of Rowan University, 1 Cooper Plaza, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Generosa","family":"Grana","sequence":"additional","affiliation":[{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Cooper University Hospital, 2 Cooper Plaza, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-1090","authenticated-orcid":false,"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Basic Science Building, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8128-6287","authenticated-orcid":false,"given":"Shumei","family":"Song","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"Department of Biomedical Sciences, Cooper Medical School of Rowan University, 401 Broadway, Camden, NJ 08103, USA"},{"name":"Camden Cancer Research Center, 403 Haddon Ave, Camden, NJ 08103, USA"},{"name":"MD Anderson Cancer Center at Cooper, Cooper University Hospital, 2 Cooper Plaza, Camden, NJ 08103, 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