{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:00:18Z","timestamp":1792803618672,"version":"4.5.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-\u03b2 signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-\u03b2 signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-\u03b2 signaling to promote HIF-2\u03b1 positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-\u03b2 downstream effector, stabilizes HIF-2\u0251 in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-\u03b2 signals converge on USP9X-HIF-2\u0251 axis via multi-level regulations, which in turn facilitates Smad\/HIF responses. Clinically, USP9X expression correlates with TGF-\u03b2 signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2\u0251. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient-derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-\u03b2 and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-\u03b2 signaling, and a downstream USP9X-HIF-2\u0251 proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-\u03b2 signaling in CSCs and meliorate clinical chemoresistance.<\/jats:p>","DOI":"10.1038\/s41419-025-07646-5","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T18:43:31Z","timestamp":1744915411000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["USP9X integrates TGF-\u03b2 and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2\u03b1-maintained stemness"],"prefix":"10.1038","volume":"16","author":[{"given":"Zhenlei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-2183","authenticated-orcid":false,"given":"Xiujie","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqi","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2019nan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhufeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronglin","family":"Kan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0625-3813","authenticated-orcid":false,"given":"Yan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0354-5113","authenticated-orcid":false,"given":"Shukai","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1378-7434","authenticated-orcid":false,"given":"Li","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,18]]},"reference":[{"key":"7646_CR1","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/nrc4019","volume":"15","author":"DD Bowtell","year":"2015","unstructured":"Bowtell DD, B\u00f6hm S, Ahmed AA, Aspuria P-J, Bast RC, Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668\u201379.","journal-title":"Nat Rev Cancer"},{"key":"7646_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.61","volume":"2","author":"UA Matulonis","year":"2016","unstructured":"Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Prim. 2016;2:16061.","journal-title":"Nat Rev Dis Prim"},{"key":"7646_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s13048-019-0588-z","volume":"12","author":"V Keyvani","year":"2019","unstructured":"Keyvani V, Farshchian M, Esmaeili S-A, Yari H, Moghbeli M, Nezhad S-RK, et al. Ovarian cancer stem cells and targeted therapy. J Ovarian Res. 2019;12:120.","journal-title":"J Ovarian Res"},{"key":"7646_CR4","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1158\/1078-0432.CCR-11-2188","volume":"18","author":"AD Steg","year":"2012","unstructured":"Steg AD, Bevis KS, Katre AA, Ziebarth A, Dobbin ZC, Alvarez RD, et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res. 2012;18:869\u201381.","journal-title":"Clin Cancer Res"},{"key":"7646_CR5","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1158\/0008-5472.CAN-19-2830","volume":"80","author":"T Nacarelli","year":"2020","unstructured":"Nacarelli T, Fukumoto T, Zundell JA, Fatkhutdinov N, Jean S, Cadungog MG, et al. NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer. Cancer Res. 2020;80:890\u2013900.","journal-title":"Cancer Res"},{"key":"7646_CR6","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1158\/0008-5472.CAN-20-1488","volume":"81","author":"Y Wang","year":"2021","unstructured":"Wang Y, Zhao G, Condello S, Huang H, Cardenas H, Tanner EJ, et al. Frizzled-7 identifies platinum-tolerant ovarian cancer cells susceptible to ferroptosis. Cancer Res. 2021;81:384\u201399.","journal-title":"Cancer Res"},{"key":"7646_CR7","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1002\/1878-0261.12419","volume":"13","author":"M He","year":"2019","unstructured":"He M, Wu H, Jiang Q, Liu Y, Han L, Yan Y, et al. Hypoxia-inducible factor-2\u03b1 directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin. Mol Oncol. 2019;13:403\u201321.","journal-title":"Mol Oncol"},{"key":"7646_CR8","doi-asserted-by":"publisher","first-page":"3991","DOI":"10.1158\/0008-5472.CAN-10-3175","volume":"71","author":"IA Silva","year":"2011","unstructured":"Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D, et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011;71:3991\u20134001.","journal-title":"Cancer Res"},{"key":"7646_CR9","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.2119\/molmed.2012.00075","volume":"18","author":"H Jiang","year":"2012","unstructured":"Jiang H, Lin X, Liu Y, Gong W, Ma X, Yu Y, et al. Transformation of epithelial ovarian cancer stemlike cells into mesenchymal lineage via EMT results in cellular heterogeneity and supports tumor engraftment. Mol Med. 2012;18:1197\u2013208.","journal-title":"Mol Med"},{"key":"7646_CR10","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1038\/onc.2011.429","volume":"31","author":"L Cao","year":"2012","unstructured":"Cao L, Shao M, Schilder J, Guise T, Mohammad KS, Matei D. Tissue transglutaminase links TGF-\u03b2, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene. 2012;31:2521\u201334.","journal-title":"Oncogene"},{"key":"7646_CR11","doi-asserted-by":"publisher","first-page":"e0230230","DOI":"10.1371\/journal.pone.0230230","volume":"15","author":"H Wen","year":"2020","unstructured":"Wen H, Qian M, He J, Li M, Yu Q, Leng Z. Inhibiting of self-renewal, migration and invasion of ovarian cancer stem cells by blocking TGF-\u03b2 pathway. PLoS ONE. 2020;15:e0230230.","journal-title":"PLoS ONE"},{"key":"7646_CR12","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.reth.2021.02.002","volume":"17","author":"GJ Yoshida","year":"2021","unstructured":"Yoshida GJ, Saya H. Molecular pathology underlying the robustness of cancer stem cells. Regen Ther. 2021;17:38\u201350.","journal-title":"Regen Ther"},{"key":"7646_CR13","doi-asserted-by":"publisher","first-page":"2780","DOI":"10.1158\/1078-0432.CCR-17-3112","volume":"24","author":"H Zhu","year":"2018","unstructured":"Zhu H, Gu X, Xia L, Zhou Y, Bouamar H, Yang J, et al. A novel TGF\u03b2 trap blocks chemotherapeutics-induced TGF\u03b21 signaling and enhances their anticancer activity in gynecologic cancers. Clin Cancer Res. 2018;24:2780\u201393.","journal-title":"Clin Cancer Res"},{"key":"7646_CR14","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1111\/cas.16074","volume":"115","author":"H Kang","year":"2024","unstructured":"Kang H, Hwang S, Kang H, Jo A, Lee JM, Choi JK, et al. Altered tumor signature and T-cell profile after chemotherapy reveal new therapeutic opportunities in high-grade serous ovarian carcinoma. Cancer Sci. 2024;115:989\u20131000.","journal-title":"Cancer Sci"},{"key":"7646_CR15","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.ygyno.2019.10.019","volume":"156","author":"S Gagno","year":"2020","unstructured":"Gagno S, Poletto E, Bartoletti M, Quartuccio L, Romualdi C, Garziera M, et al. A TGF-\u03b2 associated genetic score to define prognosis and platinum sensitivity in advanced epithelial ovarian cancer. Gynecol Oncol. 2020;156:233\u201342.","journal-title":"Gynecol Oncol"},{"key":"7646_CR16","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.ccell.2023.03.008","volume":"41","author":"A Mousset","year":"2023","unstructured":"Mousset A, Lecorgne E, Bourget I, Lopez P, Jenovai K, Cherfils-Vicini J, et al. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-\u03b2 activation. Cancer Cell. 2023;41:757\u201375.","journal-title":"Cancer Cell"},{"key":"7646_CR17","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1172\/JCI65416","volume":"123","author":"NE Bhola","year":"2013","unstructured":"Bhola NE, Balko JM, Dugger TC, Kuba MG, S\u00e1nchez V, Sanders M, et al. TGF-\u03b2 inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Investig. 2013;123:1348\u201358.","journal-title":"J Clin Investig"},{"key":"7646_CR18","doi-asserted-by":"publisher","first-page":"6365","DOI":"10.1096\/fj.201802186R","volume":"33","author":"H Zhang","year":"2019","unstructured":"Zhang H, Ren L, Ding Y, Li F, Chen X, Ouyang Y, et al. Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGF\u03b2\/Smad2-induced epithelial-mesenchymal transition in gastric cancer. FASEB J. 2019;33:6365\u201377.","journal-title":"FASEB J"},{"key":"7646_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21976-w","volume":"12","author":"B Zhang","year":"2021","unstructured":"Zhang B, Li Y, Wu Q, Xie L, Barwick B, Fu C, et al. Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer. Nat Commun. 2021;12:1714.","journal-title":"Nat Commun"},{"key":"7646_CR20","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41392-020-00436-9","volume":"6","author":"S Liu","year":"2021","unstructured":"Liu S, Ren J, Ten Dijke P. Targeting TGF\u03b2 signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6:8.","journal-title":"Signal Transduct Target Ther"},{"key":"7646_CR21","doi-asserted-by":"publisher","first-page":"4007","DOI":"10.1016\/j.cell.2023.07.036","volume":"186","author":"J Massagu\u00e9","year":"2023","unstructured":"Massagu\u00e9 J, Sheppard D. TGF-\u03b2 signaling in health and disease. Cell. 2023;186:4007\u201337.","journal-title":"Cell"},{"key":"7646_CR22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.cell.2008.10.051","volume":"136","author":"S Dupont","year":"2009","unstructured":"Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, et al. FAM\/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell. 2009;136:123\u201335.","journal-title":"Cell"},{"key":"7646_CR23","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1158\/0008-5472.CAN-16-2012","volume":"77","author":"Y Wu","year":"2017","unstructured":"Wu Y, Yu X, Yi X, Wu K, Dwabe S, Atefi M, et al. Aberrant phosphorylation of SMAD4 Thr277-mediated USP9x-SMAD4 interaction by free fatty acids promotes breast cancer metastasis. Cancer Res. 2017;77:1383\u201394.","journal-title":"Cancer Res"},{"key":"7646_CR24","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1038\/s41418-021-00740-z","volume":"28","author":"X Jie","year":"2021","unstructured":"Jie X, Fong WP, Zhou R, Zhao Y, Zhao Y, Meng R, et al. USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-\u03b22 transcription. Cell Death Differ. 2021;28:2095\u2013111.","journal-title":"Cell Death Differ"},{"key":"7646_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107685","volume":"31","author":"S Yoon","year":"2020","unstructured":"Yoon S, Parnell E, Penzes P. TGF-\u03b2-induced phosphorylation of Usp9X stabilizes ankyrin-G and regulates dendritic spine development and maintenance. Cell Rep. 2020;31:107685.","journal-title":"Cell Rep"},{"key":"7646_CR26","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1002\/path.5545","volume":"253","author":"D Cheasley","year":"2021","unstructured":"Cheasley D, Nigam A, Zethoven M, Hunter S, Etemadmoghadam D, Semple T, et al. Genomic analysis of low-grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities. J Pathol. 2021;253:41\u201354.","journal-title":"J Pathol"},{"key":"7646_CR27","doi-asserted-by":"publisher","first-page":"4268","DOI":"10.1158\/0008-5472.CAN-16-2224","volume":"77","author":"D Etemadmoghadam","year":"2017","unstructured":"Etemadmoghadam D, Azar WJ, Lei Y, Moujaber T, Garsed DW, Kennedy CJ, et al. EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas. Cancer Res. 2017;77:4268\u201378.","journal-title":"Cancer Res"},{"key":"7646_CR28","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.2174\/092986706776872943","volume":"13","author":"W Fassnacht","year":"2006","unstructured":"Fassnacht W, Mempel A, Strowitzki T, Vogt PH. Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity. Curr Med Chem. 2006;13:1397\u2013410.","journal-title":"Curr Med Chem"},{"key":"7646_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29000-5","volume":"13","author":"P Zhang","year":"2022","unstructured":"Zhang P, Guan H, Yuan S, Cheng H, Zheng J, Zhang Z, et al. Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors. Nat Commun. 2022;13:1588.","journal-title":"Nat Commun"},{"key":"7646_CR30","doi-asserted-by":"publisher","first-page":"7613.","DOI":"10.3390\/ijms21207613","volume":"21","author":"E Bahar","year":"2020","unstructured":"Bahar E, Kim J-Y, Kim H-S, Yoon H. Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression. Int J Mol Sci. 2020;21:7613.","journal-title":"Int J Mol Sci"},{"key":"7646_CR31","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1172\/JCI126414","volume":"129","author":"Z Chen","year":"2019","unstructured":"Chen Z, Wang H-W, Wang S, Fan L, Feng S, Cai X, et al. USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells. J Clin Investig. 2019;129:2043\u201355.","journal-title":"J Clin Investig"},{"key":"7646_CR32","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1172\/JCI97325","volume":"128","author":"OM Khan","year":"2018","unstructured":"Khan OM, Carvalho J, Spencer-Dene B, Mitter R, Frith D, Snijders AP, et al. The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer. J Clin Investig. 2018;128:1326\u201337.","journal-title":"J Clin Investig"},{"key":"7646_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14866","volume":"8","author":"X Li","year":"2017","unstructured":"Li X, Song N, Liu L, Liu X, Ding X, Song X, et al. USP9X regulates centrosome duplication and promotes breast carcinogenesis. Nat Commun. 2017;8:14866.","journal-title":"Nat Commun"},{"key":"7646_CR34","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1002\/jcp.30763","volume":"237","author":"T Guan","year":"2022","unstructured":"Guan T, Yang X, Liang H, Chen J, Chen Y, Zhu Y, et al. Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple-negative breast cancer by stabilizing Snail1. J Cell Physiol. 2022;237:2992\u20133000.","journal-title":"J Cell Physiol"},{"key":"7646_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109757","volume":"36","author":"H Lu","year":"2021","unstructured":"Lu H, Lyu Y, Tran L, Lan J, Xie Y, Yang Y, et al. HIF-1 recruits NANOG as a coactivator for TERT gene transcription in hypoxic breast cancer stem cells. Cell Rep. 2021;36:109757.","journal-title":"Cell Rep"},{"key":"7646_CR36","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021109187","volume":"41","author":"A Zhang","year":"2022","unstructured":"Zhang A, Huang Z, Tao W, Zhai K, Wu Q, Rich JN, et al. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J. 2022;41:e109187.","journal-title":"EMBO J"},{"key":"7646_CR37","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1186\/s13046-018-0925-x","volume":"37","author":"Y Yan","year":"2018","unstructured":"Yan Y, Liu F, Han L, Zhao L, Chen J, Olopade OI, et al. HIF-2\u03b1 promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways. J Exp Clin Cancer Res. 2018;37:256.","journal-title":"J Exp Clin Cancer Res"},{"key":"7646_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-54113-w","volume":"14","author":"A Perki\u00f6","year":"2024","unstructured":"Perki\u00f6 A, Pradhan B, Genc F, Pirttikoski A, Pikkusaari S, Erkan EP, et al. Locus-specific LINE-1 expression in clinical ovarian cancer specimens at the single-cell level. Sci Rep. 2024;14:4322.","journal-title":"Sci Rep"},{"key":"7646_CR39","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1111\/cas.12773","volume":"106","author":"C Furuta","year":"2015","unstructured":"Furuta C, Miyamoto T, Takagi T, Noguchi Y, Kaneko J, Itoh S, et al. Transforming growth factor-\u03b2 signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells. Cancer Sci. 2015;106:1524\u201333.","journal-title":"Cancer Sci"},{"key":"7646_CR40","doi-asserted-by":"publisher","DOI":"10.1093\/narcan\/zcaa021","volume":"2","author":"N Ahuja","year":"2020","unstructured":"Ahuja N, Ashok C, Natua S, Pant D, Cherian A, Pandkar MR, et al. Hypoxia-induced TGF-\u03b2-RBFOX2-ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer. NAR Cancer. 2020;2:zcaa021.","journal-title":"NAR Cancer"},{"key":"7646_CR41","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.3727\/096368912X657954","volume":"22","author":"S-P Hung","year":"2013","unstructured":"Hung S-P, Yang M-H, Tseng K-F, Lee OK. Hypoxia-induced secretion of TGF-\u03b21 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transpl. 2013;22:1869\u201382.","journal-title":"Cell Transpl"},{"key":"7646_CR42","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.1002\/jcp.30776","volume":"237","author":"L Yang","year":"2022","unstructured":"Yang L, Wang S, Pan Z, Du X, Li Q. TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells. J Cell Physiol. 2022;237:2969\u201379.","journal-title":"J Cell Physiol"},{"key":"7646_CR43","doi-asserted-by":"publisher","first-page":"2422","DOI":"10.1038\/s41388-018-0134-2","volume":"37","author":"L Li","year":"2018","unstructured":"Li L, Liu T, Li Y, Wu C, Luo K, Yin Y, et al. The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization. Oncogene. 2018;37:2422\u201331.","journal-title":"Oncogene"},{"key":"7646_CR44","doi-asserted-by":"publisher","first-page":"851","DOI":"10.15252\/emmm.201506047","volume":"8","author":"K Engel","year":"2016","unstructured":"Engel K, Rudelius M, Slawska J, Jacobs L, Ahangarian Abhari B, Altmann B, et al. USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma. EMBO Mol Med. 2016;8:851\u201362.","journal-title":"EMBO Mol Med"},{"key":"7646_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.405","volume":"7","author":"F Wolfsperger","year":"2016","unstructured":"Wolfsperger F, Hogh-Binder SA, Schittenhelm J, Psaras T, Ritter V, Bornes L, et al. Deubiquitylating enzyme USP9x regulates radiosensitivity in glioblastoma cells by Mcl-1-dependent and -independent mechanisms. Cell Death Dis. 2016;7:e2039.","journal-title":"Cell Death Dis"},{"key":"7646_CR46","doi-asserted-by":"publisher","first-page":"4528","DOI":"10.1091\/mbc.e06-05-0419","volume":"18","author":"C-J Hu","year":"2007","unstructured":"Hu C-J, Sataur A, Wang L, Chen H, Simon MC. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell. 2007;18:4528\u201342.","journal-title":"Mol Biol Cell"},{"key":"7646_CR47","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1101\/gad.1399906","volume":"20","author":"KL Covello","year":"2006","unstructured":"Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu C-J, et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20:557\u201370.","journal-title":"Genes Dev"},{"key":"7646_CR48","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1158\/0008-5472.CAN-04-3246","volume":"65","author":"KL Covello","year":"2005","unstructured":"Covello KL, Simon MC, Keith B. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res. 2005;65:2277\u201386.","journal-title":"Cancer Res"},{"key":"7646_CR49","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.pharmthera.2014.11.002","volume":"147","author":"P D\u2019Arcy","year":"2015","unstructured":"D\u2019Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther. 2015;147:32\u201354.","journal-title":"Pharmacol Ther"},{"key":"7646_CR50","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.molcel.2021.10.027","volume":"82","author":"SM Lange","year":"2022","unstructured":"Lange SM, Armstrong LA, Kulathu Y. Deubiquitinases: from mechanisms to their inhibition by small molecules. Mol Cell. 2022;82:15\u201329.","journal-title":"Mol Cell"},{"key":"7646_CR51","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1101\/gad.340133.120","volume":"34","author":"E Grunblatt","year":"2020","unstructured":"Grunblatt E, Wu N, Zhang H, Liu X, Norton JP, Ohol Y, et al. MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity. Genes Dev. 2020;34:1210\u201326.","journal-title":"Genes Dev"},{"key":"7646_CR52","doi-asserted-by":"publisher","first-page":"14999","DOI":"10.18632\/aging.203061","volume":"13","author":"Y Zhu","year":"2021","unstructured":"Zhu Y, Xu J, Hu W, Wang F, Zhou Y, Gong W, et al. Inhibiting USP8 overcomes hepatocellular carcinoma resistance via suppressing receptor tyrosine kinases. Aging. 2021;13:14999\u20135012.","journal-title":"Aging"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07646-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07646-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07646-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T07:02:23Z","timestamp":1744959743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07646-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,18]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7646"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07646-5","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,18]]},"assertion":[{"value":"23 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 April 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"312"}}