{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:16:16Z","timestamp":1788372976570,"version":"build-2803163510"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"35","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA098252"],"award-info":[{"award-number":["P50CA098252"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["1R21CA216789-01A1"],"award-info":[{"award-number":["1R21CA216789-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA098252"],"award-info":[{"award-number":["P50CA098252"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:p>\n                    High-risk human papillomaviruses (HR-HPVs) cause 95% of cervical cancers (CaCx) and a significant fraction of other anogenital and oropharyngeal cancers. Transcriptomic analyses have revealed that HR-HPVs differentially induce RNA binding proteins (RBPs) associated with cancer-related pathways. One of them, ELAVL2\/HuB, is related to the ubiquitous, well-studied ELAVL1\/HuR. But the role of either RBP in HPV pathobiology is unclear. In this study, we examined SRI-42127, an inhibitor of HuR, for its ability to curb CaCx growth in multiple model systems. We report that HR-HPV E6 and E7 oncogenes regulate the abundance and localization of HuB and HuR, that these two RBPs form a heterodimer, and that their genes are transcriptionally linked. We show that SRI-42127 reduces both RBPs, disrupts cell cycle regulation, and induces apoptosis in CaCx cell lines. We attribute these effects to a previously unrecognized ability to induce DNA damage and integrated stress response (ISR), resulting in decreased HPV E6 and E7 transcripts and proteins, while stabilizing transcriptionally active p53. Using siRNA knockdown, our results confirm that the reduction of HuB and HuR causes DNA damage and induces ISR. Furthermore, SRI-42127 curtails tumor growth of HPV16+\/hRas\n                    <jats:sup>G12V<\/jats:sup>\n                    transformed mouse TC-1 cells in syngeneic mice. Additionally, SRI-42127 complements cisplatin in inhibiting the growth of a CaCx cell line in 3D cultures and patient-derived xenografts in SCID mice. Collectively, these findings indicate that, by decreasing RBPs, while inducing DNA damage and ISR, SRI-42127 reduces HPV oncoproteins, restores p53 function in HPV+ CaCxs, thereby enhancing their sensitivity to conventional chemotherapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2401248123","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:33:41Z","timestamp":1787762021000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["HuB\/HuR inhibition decreases HPV E6 and E7 proteins, stabilizes p53, and induces integrated stress to impair cervical cancer cell growth"],"prefix":"10.1073","volume":"123","author":[{"given":"Xisheng","family":"Liu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saroj Kumar","family":"Shrestha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-3168","authenticated-orcid":false,"given":"Yvonne J. K.","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Filippova","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Neuro-Oncology, Department of Neurology, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles N.","family":"Landen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0153tk833","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics and Gynecology, University of Virginia","place":["Charlottesville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2797-5847","authenticated-orcid":false,"given":"Donald J.","family":"Buchsbaum","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Obstetrics and Gynecology, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis B.","family":"Nabors","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Neuro-Oncology, Department of Neurology, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise T.","family":"Chow","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Sanjib","family":"Banerjee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham","place":["Birmingham"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00617-5"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61416-0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012997"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-06700-8"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ypmed.2020.106313"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13091821"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.2.1551-1563.2003"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.10.012"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801156115"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215455"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2005.02.026"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02687-18"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.847761"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-0972"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1432104100"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.2.954"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.07.089"},{"key":"e_1_3_4_18_2","first-page":"1183","article-title":"Genome-scale CRISPR activation screening identifies a role of ELAVL2-CDKN1A axis in paclitaxel resistance in esophageal squamous cell carcinoma","volume":"9","author":"Zhao W. 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Liu Anti-cervical cancer activity of SRI-42127 via inducing DNA damage and activating p53 while reducing HuB HuR and HPV E6 E7 proteins. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE255374. Deposited 8 February 2024."},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00863-4"},{"key":"e_1_3_4_36_2","unstructured":"X. Liu Anti-cervical cancer activity of SRI-42127 via inducing DNA damage and activating p53 while reducing HuB HuR and HPV E6 E7 proteins. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE329096. 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