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EGFR has been demonstrated to be associated with cancer stem cell traits in HNSCC. However, the underlying molecular mechanism is far from elucidated. Here, SOX2, one of the most important stem cell markers, was identified as a binding partner and substrate of EGFR. EGFR signaling inhibition decreases SOX2 expression by promoting its autophagic degradation. Mechanistically, EGFR activation induces SOX2 phosphorylation at the Y277 site and reduces its ubiquitination, which inhibits its association with p62 and subsequent autophagic degradation. Gefitinib, an EGFR tyrosine kinase inhibitor, shows in vitro and in vivo protective effects against oral cancer cells that can be reversed through autophagy inhibition. Our study suggests that EGFR plays an important role in the development of cancer stem cells by stabilizing SOX2. Targeting EGFR in combination with conventional chemotherapy might be a promising strategy for the treatment of HNSCC through elimination of cancer stem cells.<\/jats:p>","DOI":"10.1002\/cam4.2772","type":"journal-article","created":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T08:26:01Z","timestamp":1576052761000},"page":"1131-1140","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["EGFR enhances the stemness and progression of oral cancer through inhibiting autophagic degradation of SOX2"],"prefix":"10.1002","volume":"9","author":[{"given":"Xiao\u2010Xi","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Stomatology Beijing Friendship Hospital Capital Medical University Beijing P.R. China"},{"name":"Department of Pharmacology Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College Beijing P.R. 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