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Here, we define the status of histone H2B monoubiquitylation (H2Bub1) in clear cell ovarian carcinoma (CCOC), low-grade serous carcinoma, and endometrioid carcinomas. We report that clear cell carcinomas exhibited profound loss, with nearly all cases showing low or negative H2Bub1 expression. Moreover, we found that H2Bub1 loss occurred in endometriosis and atypical endometriosis, which are established precursors to CCOCs. To examine whether dysregulation of a specific E3 ligase contributes to the loss of H2Bub1, we explored expression of ring finger protein 40 (RNF40), ARID1A, and UBR7 in the same case cohort. Loss of RNF40 was significantly and profoundly correlated with loss of H2Bub1. Using genome-wide DNA methylation profiles of 230 patients with CCOC, we identified hypermethylation of\n                    <jats:italic>RNF40<\/jats:italic>\n                    in CCOC as a likely mechanism underlying the loss of H2Bub1. Finally, we demonstrated that H2Bub1 depletion promoted cell proliferation and clonogenicity in an endometriosis cell line. Collectively, our results indicate that H2Bub1 plays a tumor-suppressive role in CCOCs and that its loss contributes to disease progression.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.164995","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T14:05:15Z","timestamp":1687356315000},"source":"Crossref","is-referenced-by-count":7,"title":["H2Bub1 loss is an early contributor to clear cell ovarian cancer progression"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9012-1441","authenticated-orcid":true,"given":"Adam J.","family":"Ferrari","sequence":"first","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"},{"name":"Graduate Program in Cell and Molecular Biology; and"},{"name":"Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4248-347X","authenticated-orcid":true,"given":"Priyanka","family":"Rawat","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah S.","family":"Rendulich","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-6511","authenticated-orcid":true,"given":"Akshaya V.","family":"Annapragada","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuto","family":"Kinose","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Devins","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Budina","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4702-2656","authenticated-orcid":true,"given":"Robert B.","family":"Scharpf","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilyn A.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janos L.","family":"Tanyi","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5245-1709","authenticated-orcid":true,"given":"Mark A.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren E.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. 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