{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:22:11Z","timestamp":1790274131180,"version":"4.1.0"},"reference-count":26,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"10","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901006"],"award-info":[{"award-number":["81901006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901006"],"award-info":[{"award-number":["81901006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis, high lymph node metastasis and early recurrence. However, the molecular events regulating HNSCC tumorigenesis remain poorly understood. Therefore, uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC. In this study, we aimed to explore the role of pleckstrin\u20102 (PLEK2) in regulating HNSCC tumorigenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort. In vitro and in vivo experiments, including cell proliferation, colony formation, Matrigel invasion, tumor sphere formation, ALDEFLUOR, Western blotting assays and xenograft mouse models, were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells. The underlying molecular mechanisms for the tumor\u2010promoting role of PLEK2 were elucidated using co\u2010immunoprecipitation, cycloheximide chase analysis, ubiquitination assays, chromatin immunoprecipitation\u2010quantitative polymerase chain reaction, luciferase reporter assays and rescue experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues, and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance. Additionally, PLEK2 was important for maintaining the proliferation, invasion, epithelial\u2010mesenchymal transition, cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells. Mechanistically, PLEK2 interacted with c\u2010Myc and reduced the association of F\u2010box and WD repeat domain containing 7 (FBXW7) with c\u2010Myc, thereby avoiding ubiquitination and subsequent proteasome\u2010mediated degradation of c\u2010Myc. Moreover, the c\u2010Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells. c\u2010Myc also directly bounded to the\n                      <jats:italic toggle=\"yes\">PLEK2<\/jats:italic>\n                      promoter and activated its transcription, forming a positive feedback loop.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Collectively, these findings uncover a previously unknown molecular basis of PLEK2\u2010enhanced c\u2010Myc signaling in HNSCC, suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12349","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:49:16Z","timestamp":1661377756000},"page":"987-1007","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c\u2010Myc\u2010mediated positive feedback loop"],"prefix":"10.34133","volume":"42","author":[{"given":"Xinyuan","family":"Zhao","sequence":"first","affiliation":[{"name":"Stomatological Hospital","place":["Guangzhou, P. R. China"]},{"name":"Southern Medical University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalong","family":"Shu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Sun","sequence":"additional","affiliation":[{"name":"The Third Affiliated Hospital","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Si","sequence":"additional","affiliation":[{"name":"Stomatological Hospital, Southern Medical University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ran","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Guo","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]},{"name":"The First Affiliated Hospital","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University","place":["Guangzhou, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-6945","authenticated-orcid":false,"given":"Li","family":"Cui","sequence":"additional","affiliation":[{"name":"Stomatological Hospital","place":["Guangzhou, P. R. China"]},{"name":"Southern Medical University","place":["Guangzhou, P. R. China"]},{"name":"University of California","place":["Los Angeles, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"issue":"4","key":"e_1_3_2_3_2","doi-asserted-by":"crossref","DOI":"10.1111\/jpi.12767","article-title":"Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L\u2010formate axis","volume":"71","author":"Cui L","year":"2021","unstructured":"Cui L, Zhao X, Jin Z, Wang H, Yang SF, Hu S. Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L\u2010formate axis. J Pineal Res. 2021;71((4)):e12767.","journal-title":"J Pineal Res"},{"issue":"1","key":"e_1_3_2_4_2","doi-asserted-by":"crossref","DOI":"10.1111\/jpi.12779","article-title":"Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics","volume":"72","author":"Shin YY","year":"2022","unstructured":"Shin YY, Seo Y, Oh SJ, Ahn JS, Song MH, Kang MJ, et\u00a0al. Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics. J Pineal Res. 2022;72((1)):e12779.","journal-title":"J Pineal Res"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"815","DOI":"10.3389\/fonc.2019.00815","article-title":"Best Practice in Systemic Therapy for Head and Neck Squamous Cell Carcinoma","volume":"9","author":"Oosting SF","year":"2019","unstructured":"Oosting SF, Haddad RI. 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