{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:58:56Z","timestamp":1783778336787,"version":"3.55.0"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"HHMI","doi-asserted-by":"publisher","award":["GT16569"],"award-info":[{"award-number":["GT16569"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention Research Institute of Texas","doi-asserted-by":"publisher","award":["RP220332"],"award-info":[{"award-number":["RP220332"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense CDMRP KCRP","doi-asserted-by":"publisher","award":["KC210123"],"award-info":[{"award-number":["KC210123"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH\/NCI","award":["R01-CA275082"],"award-info":[{"award-number":["R01-CA275082"]}]},{"name":"NIH\/NCI","award":["CA125123"],"award-info":[{"award-number":["CA125123"]}]},{"name":"NIH\/NCI","award":["S10OD032185"],"award-info":[{"award-number":["S10OD032185"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["419592238"],"award-info":[{"award-number":["419592238"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Cancer Prevention Institute of Texas","award":["RP170005"],"award-info":[{"award-number":["RP170005"]}]},{"name":"The Cancer Prevention Institute of Texas","award":["RP200504"],"award-info":[{"award-number":["RP200504"]}]},{"name":"The Cancer Prevention Institute of Texas","award":["RP250580"],"award-info":[{"award-number":["RP250580"]}]},{"name":"The Cancer Prevention Institute of Texas","award":["RP210227"],"award-info":[{"award-number":["RP210227"]}]},{"DOI":"10.13039\/100000066","name":"NIEHS","doi-asserted-by":"crossref","award":["P30 ES030285"],"award-info":[{"award-number":["P30 ES030285"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000066","name":"NIEHS","doi-asserted-by":"crossref","award":["P42 ES027725"],"award-info":[{"award-number":["P42 ES027725"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and \u03b1-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways. Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone (\u201concohistone\u201d) that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, and mitotic defects, specifically micronuclei and chromatin bridges, quantified with cytogenetic analysis. Results: EPZ-719 caused a dose- and time-dependent reduction in SETD2 activity on both histone and tubulin substrates, accompanied by significant increases in chromatin bridges and micronuclei in retinal pigmented epithelial (RPE-1) and 786-O ccRCC cells. Similarly, oncohistone expression markedly decreased SETD2 function, as determined by H3K36me3 levels, and induced comparable mitotic defects in 786-O cells, and aneuploidy in two chondrocyte cell lines expressing the H3.3K36M oncohistone. Combining EPZ-719 with H3.3K36M expression did not exacerbate mitotic defects beyond either oncohistone or pharmacologic inhibition alone, consistent with inhibition of SETD2 as their shared underlying mechanism of action. Conclusions: Pharmacologic inhibition and oncohistone-mediated sequestration of SETD2 converge on the induction of mitotic defects, underscoring SETD2\u2019s essential role in maintaining genomic stability. Identification of loss of genomic stability as a canonical feature of SETD2 inactivation points to a potential therapeutic liability associated with targeting SETD2 in cancers where it is overexpressed and reveals a mechanism that could contribute to the progression of cancers expressing oncohistone mutations.<\/jats:p>","DOI":"10.3390\/cancers18050819","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T08:51:33Z","timestamp":1772614293000},"page":"819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacologic and Oncohistone Inhibition of SETD2 Converge on Genomic Instability"],"prefix":"10.3390","volume":"18","author":[{"given":"Alyssa T.","family":"Paparella","sequence":"first","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1985-1641","authenticated-orcid":false,"given":"Ashley G.","family":"Boice","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Young","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6791-4348","authenticated-orcid":false,"given":"Rajkishor","family":"Nishad","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Durga","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth A.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1563-0219","authenticated-orcid":false,"given":"Edward W.","family":"Pietryk","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-4448","authenticated-orcid":false,"given":"H. Josh","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-5509","authenticated-orcid":false,"given":"Ian J.","family":"Frew","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Centre, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Kimryn","family":"Rathmell","sequence":"additional","affiliation":[{"name":"Arthur G. James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank M.","family":"Mason","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1457-609X","authenticated-orcid":false,"given":"Ruhee","family":"Dere","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4233-3247","authenticated-orcid":false,"given":"Cheryl Lyn","family":"Walker","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1073\/pnas.0915033107","article-title":"Histone H3 Lysine 36 Methyltransferase Hypb\/Setd2 Is Required for Embryonic Vascular Remodeling","volume":"107","author":"Hu","year":"2010","journal-title":"Proc. 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