HPV E6 Protein Associated SOX21-AS1 Promotes YAP/TAZ Activation by Attenuating YAP1 Ubiquitination in Human Cervical Cancer

Abstract Background: The human papillomavirus (HPV), especially HPV 16 type infection, is one of the well-known causes for human cervical cancer, we sought to investigate HPV 16 regulating lncRNA and its role in cervical carcinogenesis. Methods: The potential HPV16 related lncRNAs were screened by using bioinfomatic analysis. The relationship between SOX21-AS1 and clinical features was studied by using clinical samples. Its oncogenic roles were explored in vitro. Results: A HPV 16 infection-specific lncRNA, SOX21-AS1 was spotted by screening the Cancer Genome Atlas TCGA database, and its expression was seriously related to Hippo signaling pathway by using Gene Set Enrichment Analysis. Total 40 cases patients suffered from cervical carcinomas (CCs) were involved, we found that SOX21-AS1 was over-expressed in those CCs patients who were positive for HPV 16 infection compared to those who were negative. We also found that SOX21-AS1 expression was positively related to E6 protein but not E7 expression, which is a carcinogenic protein of HPV 16. Also, YAP1/TAZ/TEAD complex can increase SOX21-AS1 transcription by binding to its promoter region. SOX21-AS1 can promote cell proliferation and invasion in CCs cell lines in a YAP1 activation-dependent manner. We found that SOX21-AS1 can promote YAP1 activation by preventing YAP1 phosphorylation at s127 residue and further preventing its degradation by binding to 14-3-3. Conclusion: In conclusion, SOX21-AS1 is an HPV16 specific lncRNA which can promote tumor growth and metastasis by targeting the Hippo signaling pathway.