{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:30:54Z","timestamp":1768523454543,"version":"3.49.0"},"posted":{"date-parts":[[2025,8,1]]},"group-title":"Cancer Biology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hepatoblastoma (HB) is the most common pediatric liver malignancy. However, its cellular origin and molecular drivers remain poorly defined. Using single-nuclear RNA sequencing (snRNA-seq), we identified a proliferative, hepatocyte-derived tumor cell population (cycling Hep\n                  <jats:sup>T<\/jats:sup>\n                  ) enriched for Enhancer of Zeste Homolog 2 (\n                  <jats:italic>EZH2)<\/jats:italic>\n                  expression, particularly in the aggressive embryonal subtype. Integrative genomic and transcriptomic profiling confirmed\n                  <jats:italic>EZH2<\/jats:italic>\n                  overexpression. Disruption of the PRC2 complex was evident through mislocalization and reduced expression of SUZ12, a core component.\n                  <jats:italic>EZH2<\/jats:italic>\n                  overexpression correlated with upregulation of mitotic regulators such as\n                  <jats:italic>AURKB<\/jats:italic>\n                  and\n                  <jats:italic>Ki67<\/jats:italic>\n                  in human HB gene expression analysis as compared to background liver. Targeted sequencing identified variants of uncertain significance in\n                  <jats:italic>EZH2<\/jats:italic>\n                  and\n                  <jats:italic>SUZ12<\/jats:italic>\n                  in 11 of 11 patient tumors. Pharmacologic inhibition of EZH2 with EPZ-6438 reduced proliferation and sensitized HB cells to cisplatin through gene regulation, potentially modulating platinum accumulation both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . In summary, EZH2 promotes HB progression through epigenetic silencing and noncanonical signaling pathways. These findings support EZH2\u2019s contribution to HB pathogenesis, therefore identifying it as a novel therapeutic target.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>STATEMENT OF SIGNIFICANCE<\/jats:title>\n                  <jats:p>EZH2 is enriched in hepatoblastoma, suggesting its role in early tumorigenesis. Its inhibition, combined with cisplatin, produces synergistic anti-tumor effects, supporting EZH2 as both an oncogenic and therapeutic target.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.30.667506","type":"posted-content","created":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T06:30:11Z","timestamp":1754116211000},"source":"Crossref","is-referenced-by-count":0,"title":["Oncogenic Role of Aberrant EZH2 in Hepatoblastoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-7489","authenticated-orcid":false,"given":"Kathryn","family":"Glaser","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7341-1642","authenticated-orcid":false,"given":"Lara","family":"Berklite","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7639-5147","authenticated-orcid":false,"given":"Brian T.","family":"Hickner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka","family":"Rao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roma H.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5857-9495","authenticated-orcid":false,"given":"Andrew A.","family":"Badachhape","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5681-0112","authenticated-orcid":false,"given":"Somak","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Schepers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolai A.","family":"Timchenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James I.","family":"Geller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6214-9167","authenticated-orcid":false,"given":"Sarangarajan","family":"Ranganathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory M.","family":"Tiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5109-6514","authenticated-orcid":false,"given":"Bruce","family":"Aronow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6989-3041","authenticated-orcid":false,"given":"Takanori","family":"Takebe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0515-5795","authenticated-orcid":false,"given":"Sarah E.","family":"Woodfield","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3578-4258","authenticated-orcid":false,"given":"Sanjeev A.","family":"Vasudevan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2430-6982","authenticated-orcid":false,"given":"Erica A.K.","family":"DePasquale","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander J.","family":"Bondoc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025080514500788000_2025.07.30.667506v1.1","doi-asserted-by":"crossref","unstructured":"Lim IIP , Bondoc AJ , Geller JI , Tiao GM . 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