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Inactivation of the tumor suppressor p53 is the most frequent driver event in this malignancy. p53 inactivation occurs either through\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations in human papilloma virus (HPV)\u2010negative cases or via HPV\u2010mediated p53 degradation in HPV\u2010positive (HPV+) cases, where most tumors retain a wild\u2010type (WT)\n                    <jats:italic>TP53<\/jats:italic>\n                    allele. This underscores the critical role ofp53\u2010regulated processes in HNSCC pathogenesis. Clinically, HPV+ HNSCC has significantly better outcomes than HPV\u2010negative disease. However, approximately 10% of HPV+ HNSCC tumors harbor\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations, suggesting selective pressure to suppress p53 signaling beyond viral degradation. In this study, we demonstrate that HPV+\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010WTHNSCC cells have residual, tumor suppressive p53 activity. Clinically, patients with HPV+\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010WT tumors exhibit significantly better survival than those with HPV+\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010mutantor HPV\u2010negative tumors. In vitro, WT p53 loss in HPV+ HNSCC cells enhances proliferation, migration, and invasion, and transcriptomic analysis confirms ongoing p53\u2010dependent gene regulation. HPV+\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010WT tumors also display tumor\u2010suppressive gene methylation patterns, fewer chromosomal alterations, and reduced PI3K\u2010AKT signaling compared to\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010mutant HPV+ cases. Notably, p53 loss increases expression of the PI3K catalytic subunit p110\u03b1, suppresses the PI3K\u2010AKT inhibitor\n                    <jats:italic>INPP5D<\/jats:italic>\n                    , and sensitizes cells to pharmacologic PI3Kinhibition. Together, our findings challenge the prevailing view that p53 is completely inactivated in HPV+ HNSCC and reveal tumor suppressive, p53\u2010driven mechanisms that persist in these tumors. These insights highlight a potential role for\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010based stratification in guiding treatment decisions and suggest new therapeutic vulnerabilities in HPV+ HNSCC.\n                  <\/jats:p>","DOI":"10.1002\/hed.70085","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:06:26Z","timestamp":1761894386000},"page":"863-875","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Human Papilloma Virus Does Not Fully Inactivate p53 Cellular Activity in\n                    <scp>HNSCC<\/scp>"],"prefix":"10.1002","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1333-415X","authenticated-orcid":false,"given":"Jovanka","family":"Gencel\u2010Augusto","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liam C.","family":"Woerner","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuo","family":"Tian","sequence":"additional","affiliation":[{"name":"UCSF School of Medicine  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashir A.","family":"Borah","sequence":"additional","affiliation":[{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey N.","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0306-6147","authenticated-orcid":false,"given":"Patrick","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer R.","family":"Grandis","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery University of California San Francisco (UCSF)  San Francisco California USA"},{"name":"UCSF Helen Diller Family Comprehensive Cancer Center  San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010020\u201000224\u20103"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201012\u20100095"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073770"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0912217"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.340976.120"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201045920\u2010w"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1797"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/378203a0"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4368"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201020\u20101804"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010017\u20100004\u20104"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.007"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100638R"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201022\u20100872"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2018.06.001"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25592"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2018.0395"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13355"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000935"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.25833"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep12870"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0065\u20102571(02)00043\u20102"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2011.02.008"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201013\u20100073"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201014\u20102735"},{"key":"e_1_2_15_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.17.11535"},{"key":"e_1_2_15_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32068"},{"key":"e_1_2_15_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.30716"},{"key":"e_1_2_15_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201033544\u2010x"},{"key":"e_1_2_15_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(90)90409\u20108"},{"key":"e_1_2_15_32_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.8315"},{"key":"e_1_2_15_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1336577"},{"key":"e_1_2_15_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcms.2005.05.004"},{"key":"e_1_2_15_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2008474117"},{"key":"e_1_2_15_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80402"},{"key":"e_1_2_15_37_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.24309"},{"key":"e_1_2_15_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201017\u20101672"},{"key":"e_1_2_15_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010024\u201001259\u20109"},{"key":"e_1_2_15_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/PEC.0000000000003192"},{"key":"e_1_2_15_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)32779\u2010X"},{"key":"e_1_2_15_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201013\u20100587"},{"key":"e_1_2_15_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2025.151703"},{"key":"e_1_2_15_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"}],"container-title":["Head 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