Pathogen Genomics Center, National Institute of Infectious Diseases , Tokyo, Japan.
J Virol. 2023 Aug 31;97(8):e0081523. doi: 10.1128/jvi.00815-23. Epub 2023 Aug 14.
Transcription of the human papillomavirus (HPV) oncogenes, and , is regulated by the long control region (LCR) of the viral genome. Although various transcription factors have been reported to bind to the LCR, little is known about the transcriptional cofactors that modulate HPV oncogene expression in association with these transcription factors. Here, we performed DNA-pulldown purification of nuclear proteins in cervical cancer cells, followed by proteomic analyses to identify transcriptional cofactors that bind to the HPV16 LCR via the transcription factor TEAD1. We detected the proinflammatory cytokine S100A9 that localized to the nucleus of cervical cancer cells and associated with the LCR via direct interaction with TEAD1. Nuclear S100A9 levels and its association with the LCR were increased in cervical cancer cells by treatment with a proinflammatory phorbol ester. Knockdown of S100A9 decreased HPV oncogene expression and reduced the growth of cervical cancer cells and their susceptibility to cisplatin, whereas forced nuclear expression of S100A9 using nuclear localization signals exerted opposite effects. Thus, we conclude that nuclear S100A9 binds to the HPV LCR via TEAD1 and enhances viral oncogene expression by acting as a transcriptional coactivator. IMPORTANCE Human papillomavirus (HPV) infection is the primary cause of cervical cancer, and the viral oncogenes and play crucial roles in carcinogenesis. Although cervical inflammation contributes to the development of cervical cancer, the molecular mechanisms underlying the role of these inflammatory responses in HPV carcinogenesis are not fully understood. Our study shows that S100A9, a proinflammatory cytokine, is induced in the nucleus of cervical cancer cells by inflammatory stimuli, and it enhances HPV oncogene expression by acting as a transcriptional coactivator of TEAD1. These findings provide new molecular insights into the relationship between inflammation and viral carcinogenesis.
人乳头瘤病毒（HPV）的癌基因转录， 和 ，受到病毒基因组的长控制区（LCR）的调节。虽然已经报道了各种转录因子与 LCR 结合，但对于调节 HPV 癌基因表达的转录共因子知之甚少，这些转录共因子与这些转录因子有关。在这里，我们在宫颈癌细胞中进行了核蛋白的 DNA 下拉纯化，然后进行蛋白质组学分析，以鉴定通过转录因子 TEAD1 与 HPV16 LCR 结合的转录共因子。我们检测到促炎细胞因子 S100A9，其定位于宫颈癌细胞核内，并通过与 TEAD1 的直接相互作用与 LCR 结合。通过促炎佛波醇酯处理，宫颈癌细胞中的核 S100A9 水平及其与 LCR 的关联增加。S100A9 的敲低降低了 HPV 癌基因的表达，并降低了宫颈癌细胞的生长及其对顺铂的敏感性，而使用核定位信号强制核表达 S100A9 则产生相反的效果。因此，我们得出结论，核 S100A9 通过 TEAD1 与 HPV LCR 结合，并作为转录共激活剂增强病毒癌基因的表达。重要性人乳头瘤病毒（HPV）感染是宫颈癌的主要原因，病毒癌基因 和 在致癌作用中起着至关重要的作用。尽管宫颈炎症有助于宫颈癌的发展，但这些炎症反应在 HPV 致癌作用中的作用的分子机制尚未完全了解。我们的研究表明，促炎细胞因子 S100A9 被炎性刺激物诱导到宫颈癌细胞核内，并通过作为 TEAD1 的转录共激活剂增强 HPV 癌基因的表达。这些发现为炎症与病毒致癌之间的关系提供了新的分子见解。
