{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:25:30Z","timestamp":1787163930925,"version":"build-2736575974"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173638"],"award-info":[{"award-number":["82173638"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473442"],"award-info":[{"award-number":["82473442"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173341"],"award-info":[{"award-number":["82173341"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"HSTD | Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2023JJ20087"],"award-info":[{"award-number":["2023JJ20087"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Changsha Distinguished Young Scholars grant","award":["ka2209007"],"award-info":[{"award-number":["ka2209007"]}]},{"name":"science and technology innovation Program of Hunan Province","award":["2023RC3082"],"award-info":[{"award-number":["2023RC3082"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:p>The development of metastasis marks an aggressive stage of head and neck squamous cell carcinoma (HNSCC) and is closely linked to unfavorable survival outcomes. While metadherin (MTDH) drives tumorigenesis, metastasis, and chemoresistance in HNSCC, its dysregulation mechanisms remain unclear. Here, we identify USP14 as a specific deubiquitinase that stabilizes MTDH. USP14-dependent deubiquitination of MTDH activates NF-\u03baB signaling, which drives epithelial\u2013mesenchymal transition and supports cancer stem cells maintenance, ultimately strengthening HNSCC metastasis and chemoresistance. Mechanistically, we uncovered a competitive interaction: USP14 competes with the ubiquitin ligase FBXW7 for MTDH binding, preventing FBXW7-mediated degradation. Consequently, USP14 inhibition significantly mitigates aggressive phenotypes, an effect reversed by MTDH reintroduction. Clinical analysis confirms that MTDH and USP14 are overexpressed and positively correlated in metastatic HNSCC tissues. In conclusion, our study reveals a regulatory axis where USP14 competitively counteracts FBXW7 to stabilize MTDH, driving HNSCC progression. These findings provide preclinical evidence that targeting USP14 is a promising therapeutic strategy to overcome metastasis and chemoresistance in HNSCC.<\/jats:p>","DOI":"10.1073\/pnas.2504068123","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:37:08Z","timestamp":1787161028000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["USP14 competitively binds to FBXW7 to stabilize MTDH and promotes metastasis and drug resistance of head and neck squamous cell carcinoma"],"prefix":"10.1073","volume":"123","author":[{"given":"Xueying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05jb9pq57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Radiation Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diekuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juncheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]},{"name":"National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)","place":["Changsha, People\u2019s Republic of China"]},{"name":"Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7347-3816","authenticated-orcid":false,"given":"Gangcai","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5102-0309","authenticated-orcid":false,"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University","place":["Changsha, People\u2019s Republic of China"]},{"name":"Otolaryngology Major Disease Research Key Laboratory of Hunan Province","place":["Changsha, People\u2019s Republic of China"]},{"name":"National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)","place":["Changsha, People\u2019s Republic of China"]},{"name":"Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan Province","place":["Changsha, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1715715"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2018.11"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01835-2"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0227-z"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2022.166431"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2024.04.001"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14168"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-1327"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20193153"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-019-03514-x"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgp064"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-010-9475-6"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16605"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00280-y"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00279-5"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.063313.117"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C111.291518"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-4009"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004496"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3029"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-6164"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7658"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29230"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-0659"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-0049"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2013.09.033"},{"key":"e_1_3_4_28_2","first-page":"5236","article-title":"Risk model-guided identification of MTDH expression as a marker for ferroptosis induction therapy in head and neck squamous cell carcinoma","volume":"13","author":"Wang X.","year":"2023","unstructured":"X. Wang , Risk model-guided identification of MTDH expression as a marker for ferroptosis induction therapy in head and neck squamous cell carcinoma. Am. J. Cancer Res. 13, 5236\u20135253 (2023).","journal-title":"Am. J. Cancer Res."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103102"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14259"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3892\/or.2017.5949"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000000502"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.4149\/neo_2018_170228N149"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008541"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.027"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-021-01455-y"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00320-7"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215750"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0930"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12020268"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00366-w"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-021-00508-3"},{"key":"e_1_3_4_43_2","first-page":"2554","article-title":"MiR-98 inhibits malignant progression via targeting MTDH in squamous cell carcinoma of the head and neck","volume":"7","author":"Tan H.","year":"2017","unstructured":"H. Tan , MiR-98 inhibits malignant progression via targeting MTDH in squamous cell carcinoma of the head and neck. Am. J. Cancer Res. 7, 2554\u20132565 (2017).","journal-title":"Am. J. Cancer Res."},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.11.013"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0396-8"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b01138"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.08.100"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01144-x"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2017.09.015"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33285-x"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15174385"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09299"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-024-05710-9"},{"key":"e_1_3_4_54_2","unstructured":"X. Wang Data from \u201cUSP14 competitively binds to FBXW7 to stabilize MTDH and promotes metastasis and drug resistance of head and neck squamous cell carcinoma.\u201d China National Center for Bioinformation. https:\/\/ngdc.cncb.ac.cn\/omix\/release\/OMIX019314. Accessed 4 August 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2504068123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:37:12Z","timestamp":1787161032000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2504068123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":54,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2026,8,25]]}},"alternative-id":["10.1073\/pnas.2504068123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2504068123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"assertion":[{"value":"2025-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2504068123"}}