{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T10:03:02Z","timestamp":1784282582065,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proteasome inhibitors are approved to treat multiple myeloma and mantle cell lymphoma. Recent reports suggest sarcomas also display proteasome addiction. Mechanistic explanations cite proteotoxic stress. In sarcoma patients, we analyzed the impacts of 377 human E3 ubiquitin ligases on sarcoma patient overall survival (OS) and recurrence-free survival (RFS), identified substrates of E3 ligases with the most significant and robust effects, and performed enrichment analyses. High expression of 102 E3 ligases was associated with shortened OS. Thirteen of these shortened OS by &gt;40 months, six with false-discovery rates (FDR) \u2264 5%. Nineteen showed correlation between increased expression and shortened RFS, two with FDR \u2264 5%. Overexpression of 73 E3 ligases significantly extended OS, with 18 extending OS by &gt;40 months; six with FDR \u2264 5%. Elevated expression of 21 significantly extended RFS, one with FDR \u2264 5%. Enrichment analyses of substrates unique to the E3 ligases whose elevated expression most reliably shortened or extended OS by &gt;40 months revealed non-overlapping functions: the E3 ligases associated with shortened OS uniquely targeted cell cycle, cell\u2013cell communication, cellular responses to stimuli, chromatin organization, DNA repair, DNA replication, hemostasis, reproduction, and vesicle-mediated transport functions. Both OS-impacting E3 ligase sets targeted developmental biology, gene expression, immune system, metabolism of proteins, and signal transduction functions. Three specific functions were targeted by both groups. Functions uniquely targeted by each set of ligases could reveal therapeutic targets with a greater therapeutic index than the proteasome.<\/jats:p>","DOI":"10.3390\/ijms27146350","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:00:52Z","timestamp":1784278852000},"page":"6350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of E3 Ubiquitin Ligases Associated with Survival in Soft Tissue Sarcomas"],"prefix":"10.3390","volume":"27","author":[{"given":"Zackary","family":"Bender","sequence":"first","affiliation":[{"name":"Biology Department, Waldorf University, 106 South 6th Street, Forest City, IA 50436, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-534X","authenticated-orcid":false,"given":"Hannah C.","family":"Beird","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, The University of Texas, UT MD Anderson Cancer Center, 1881 East Road, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Larsen","sequence":"additional","affiliation":[{"name":"MercyOne North Iowa Medical Center, 1000 4th Street SW, Mason City, IA 50401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0711-185X","authenticated-orcid":false,"given":"Gary S.","family":"Coombs","sequence":"additional","affiliation":[{"name":"Biology Department, Waldorf University, 106 South 6th Street, Forest City, IA 50436, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41392-021-00647-8","article-title":"Molecular mechanisms underpinning sarcomas and implications for current and future therapy","volume":"6","author":"Damerell","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/stem.596","article-title":"Concise review: Mesenchymal tumors: When stem cells go mad","volume":"29","author":"Mohseny","year":"2011","journal-title":"Stem Cells"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1177\/1758834017728927","article-title":"Managing sarcoma: Where have we come from and where are we going?","volume":"9","author":"Bleloch","year":"2017","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1002\/pbc.23252","article-title":"Soft tissue sarcoma across the age spectrum: A population-based study from the Surveillance Epidemiology and End Results database","volume":"57","author":"Ferrari","year":"2011","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_5","unstructured":"Min, V.L.K., Puhaindran, M.E., Ai, C.B., Pang, A.S.L., and Hallinan, J.T.P.D. (2025). Clinical Management of Bone and Soft Tissue Tumors, Springer Nature. [1st ed.]."},{"key":"ref_6","unstructured":"National Foundation for Cancer Research (2025, November 01). About Sarcoma. Available online: https:\/\/www.nfcr.org\/cancer-types\/cancer-types-sarcoma\/."},{"key":"ref_7","unstructured":"Painter, C. (2025, November 01). What Makes Immunotherapy for Sarcoma a Promising Treatment? Cancer Research Institute. Available online: https:\/\/www.cancerresearch.org\/immunotherapy-by-cancer-type\/sarcoma."},{"key":"ref_8","unstructured":"Sarcoma Foundation of America (2025, November 01). 2023 Sarcoma Statistics. Available online: https:\/\/curesarcoma.org\/sarcoma-education\/2023-sarcoma-statistics\/."},{"key":"ref_9","unstructured":"Gounder, M.M. (2025, November 01). Soft Tissue Sarcoma Treatment Protocols. Medscape 2022. Available online: https:\/\/emedicine.medscape.com\/article\/2007168-overview."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4310","DOI":"10.1158\/1078-0432.CCR-23-3983","article-title":"First-line anlotinib treatment for soft-tissue sarcoma in chemotherapy-ineligible patients: An open-label, single-arm, phase 2 clinical trial","volume":"30","author":"Li","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"899","DOI":"10.6004\/jnccn.2020.7590","article-title":"Evolving role of immunotherapy in recurrent metastatic head and neck cancer","volume":"18","author":"Le","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_12","unstructured":"American Cancer Society (2025, November 01). Survival Rates for Soft Tissue Sarcoma. Available online: https:\/\/www.cancer.org\/cancer\/types\/soft-tissue-sarcoma\/detection-diagnosis-staging\/survival-rates.html#:~:text=For%20example%2C%20if%20the%205%2Dyear%20relative%20survival,means%20that%20people%20who%20have%20that%20cancer."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4525","DOI":"10.1158\/0008-5472.CAN-16-1040","article-title":"Proteasome addiction defined in Ewing sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors","volume":"76","author":"Shukla","year":"2016","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/ijc.25024","article-title":"Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma","volume":"127","author":"Shapovalov","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.7150\/ijbs.90226","article-title":"PSME2 offers value as a biomarker of M1 macrophage infiltration in pan-cancer and inhibits osteosarcoma malignant phenotypes","volume":"20","author":"Li","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3892\/mmr.2025.13524","article-title":"MG132 induces cell type-specific anticancer effects in uterine leiomyosarcoma cell lines","volume":"31","author":"Joung","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13569-016-0057-z","article-title":"High nuclear expression of proteasome activator complex subunit 1 predicts poor survival in soft tissue leiomyosarcomas","volume":"6","author":"Lou","year":"2016","journal-title":"Clin. Sarcoma Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2207200119","DOI":"10.1073\/pnas.2207200119","article-title":"Structural insights into the human PA28-20S proteasome enabled by efficient tagging and purification of endogenous proteins","volume":"119","author":"Zhao","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.molcel.2014.12.039","article-title":"Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G","volume":"57","author":"Sahtoe","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1038\/sj.emboj.7600832","article-title":"Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14","volume":"24","author":"Hu","year":"2005","journal-title":"EMBO J."},{"key":"ref_21","unstructured":"Medvar, B., Pisitkun, T., Sarkar, A., and Knepper, M.A. (2025, May 22). Human E3 Ubiquitin Ligases. National Heart Lung Blood Institute, Epithelial Systems Biology Laboratory (ESBL), Available online: https:\/\/esbl.nhlbi.nih.gov\/Databases\/KSBP2\/Targets\/Lists\/E3-ligases\/."},{"key":"ref_22","unstructured":"Cancer Genome Atlas Research Network (2017). Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell, 171, 950\u2013965.e28."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D719","DOI":"10.1093\/nar\/gkab962","article-title":"UbiBrowser 2.0: A comprehensive resource for proteome-wide ubiquitin ligase\/deubiquitinase-substrate interactions in eukaryotic species","volume":"50","author":"Wang","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10637-022-01222-w","article-title":"The therapeutic potential of RNA polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma","volume":"40","author":"Kang","year":"2022","journal-title":"Investig. New Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/s41568-020-0288-4","article-title":"The epigenomics of sarcoma","volume":"20","author":"Nacev","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8597","DOI":"10.1002\/jcp.27841","article-title":"RUNX1-dependent mechanisms in biological control and dysregulation in cancer","volume":"234","author":"Hong","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1111\/j.1349-7006.2011.02189.x","article-title":"Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract","volume":"103","author":"Fijneman","year":"2012","journal-title":"Cancer Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14175","DOI":"10.18632\/oncotarget.24419","article-title":"RUNX1 and RUNX3 protect against YAP-mediated EMT, stem-ness and shorter survival outcomes in breast cancer","volume":"9","author":"Kulkarni","year":"2018","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s00018-022-04141-4","article-title":"Revisiting ZAR proteins: The understudied regulator of female fertility and beyond","volume":"79","author":"Wu","year":"2022","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, N., Jiang, T., Wang, Y., Wang, S., Hu, L., and Bu, Y. (2020). BTG4 is a novel p53 target gene that inhibits cell growth and induces apoptosis. Genes, 11.","DOI":"10.3390\/genes11020217"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113800","DOI":"10.1016\/j.biopha.2022.113800","article-title":"HOXA5: A crucial transcriptional factor in cancer and a potential therapeutic target","volume":"155","author":"Fan","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41420-022-00930-9","article-title":"Targeting tumor innervation: Premises, promises, and challenges","volume":"8","author":"Li","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_33","first-page":"e89290","article-title":"The role of the CDH1 gene in the pathogenesis and progression of lobular breast cancer","volume":"17","author":"Mitchell","year":"2025","journal-title":"Cureus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s40364-025-00860-5","article-title":"Arginine methylation in cancer: Mechanisms and therapeutic implications","volume":"13","author":"Xu","year":"2025","journal-title":"Biomark. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1111\/j.1349-7006.2009.01123.x","article-title":"Cellular senescence: Its role in tumor suppression and aging","volume":"100","author":"Ohtani","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yang, J., Liu, M., Hong, D., Zeng, M., and Zhang, X. (2021). The paradoxical role of cellular senescence in cancer. Front. Cell Dev. Biol., 9, Corrigendum in Front. Cell Dev. Biol.\u00a02021, 9, 759761. https:\/\/doi.org\/10.3389\/fcell.2021.759761.","DOI":"10.3389\/fcell.2021.759761"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1007\/s00018-015-2112-y","article-title":"FOXO transcription factors in cancer development and therapy","volume":"73","author":"Demoulin","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Schreiber, S., Hammers, C.M., Kaasch, A.J., Schraven, B., Dudeck, A., and Kahlfuss, S. (2021). Metabolic interdependency of Th2 cell-mediated type 2 immunity and the tumor microenvironment. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.632581"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1084\/jem.190.5.617","article-title":"Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo","volume":"190","author":"Nishimura","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1002\/med.22059","article-title":"Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future","volume":"44","author":"Morel","year":"2024","journal-title":"Med. Res. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1091\/mbc.e12-10-0771","article-title":"p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1","volume":"24","author":"Santiago","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1158\/0008-5472.CAN-07-6268","article-title":"Soft tissue sarcoma cells are highly sensitive to AKT blockade: A role for p53-independent up-regulation of GADD45 alpha","volume":"68","author":"Zhu","year":"2008","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1158\/1541-7786.MCR-21-0844","article-title":"The role of AKT in soft tissue sarcoma: Review and insights","volume":"20","author":"Wang","year":"2022","journal-title":"Mol. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11628","DOI":"10.1038\/s41598-025-96427-3","article-title":"Safety assessment of proteasome inhibitors real world adverse event analysis from the FAERS database","volume":"15","author":"Huang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaccao.2022.12.005","article-title":"Cardiovascular toxicity of proteasome inhibitors: Underlying mechanisms and management strategies: JACC: CardioOncology State-of-the-Art Review","volume":"5","author":"Georgiopoulos","year":"2023","journal-title":"JACC CardioOncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/s43018-025-00981-8","article-title":"The diverse roles of the circadian clock in cancer","volume":"6","author":"Fortin","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Freije, J.M.P., Fraile, J.M., and L\u00f3pez-Ot\u00edn, C. (2011). Protease addiction and synthetic lethality in cancer. Front. Oncol., 1.","DOI":"10.3389\/fonc.2011.00025"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Guang, M.H.Z., Kavanagh, E.L., Dunne, L.P., Dowling, P., Zhang, L., Lindsay, S., Bazou, D., Goh, C.Y., Hanley, C., and Bianchi, G. (2019). Targeting proteotoxic stress in cancer: A review of the role that protein quality control pathways play in oncogenesis. Cancers, 11.","DOI":"10.3390\/cancers11010066"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature19947","article-title":"Proteome complexity and the forces that drive proteome imbalance","volume":"537","author":"Harper","year":"2016","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.1007\/s11010-025-05336-6","article-title":"Synthetic inhibition of the SUMO pathway by targeting the SAE1 component via TAK-981 compound impairs growth and chemosensitizes embryonal and alveolar rhabdomyosarcoma cell lines","volume":"480","author":"Codenotti","year":"2025","journal-title":"Mol. Cell. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Odhiambo, D.A., Fan, S., and Hirbe, A.C. (2025). UBR5 in tumor biology: Exploring mechanisms of immune regulation and possible therapeutic implications in MPNST. Cancers, 17.","DOI":"10.3390\/cancers17020161"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e38393","DOI":"10.1097\/MD.0000000000038393","article-title":"The expression and clinical significance of UHRF1 in soft tissue sarcomas and its prognostic value","volume":"103","author":"Shu","year":"2024","journal-title":"Medicine"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.ccell.2021.07.003","article-title":"TRIM8 modulates the EWS\/FLI oncoprotein to promote survival in Ewing sarcoma","volume":"39","author":"Seong","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102344","DOI":"10.1016\/j.redox.2022.102344","article-title":"TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS\/AMPK\/mTOR\/autophagy signaling","volume":"53","author":"Liu","year":"2022","journal-title":"Redox Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4101","DOI":"10.1016\/j.csbj.2021.07.014","article-title":"Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer","volume":"19","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_57","first-page":"100625","article-title":"Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors","volume":"5","year":"2024","journal-title":"Innovation"},{"key":"ref_58","unstructured":"Kassambara, A., Kosinski, M., and Biecek, P. (2025, May 22). Survminer: Drawing Survival Curves Using \u2018ggplot2\u2019. 2025. R Package Version 0.5.1. Available online: https:\/\/rpkgs.datanovia.com\/survminer\/index.html."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis, Springer.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","author":"Milacic","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-4939-6783-4_11","article-title":"Functional interaction network construction and analysis for disease discovery","volume":"1558","author":"Wu","year":"2017","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:05:15Z","timestamp":1784279115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":61,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146350"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146350","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}