Enhancing Oncolytic Adenovirus Replication by Early Region 1A Protein‐Mediated Degradation of E1A Binding Protein p300

Oncolytic adenovirus (OAd) therapy is one of the effective treatment strategies for solid malignant tumors, and E1A is a requirement for adenovirus replication. Thus, it is very important to study how E1A regulates adenovirus replication. The p300 and E1A expression were detected by Western blot. The viral replication of OAd was detected by virus replication assay. The interaction between E1A and p300 was analyzed by immunofluorescence and immunoprecipitation assays. The therapeutic effect of OAd-shp300 was analyzed by MTT assay and animal experiments. The results indicated that OAd infection or E1A overexpression could reduce p300 expression, implying that OAd might reduce p300 expression via E1A, and p300 knockdown could enhance viral replication and cell cytotoxicity of OAd. Furthermore, E1A promoted viral replication of OAd via mediating p300 ubiquitination degradation to inhibit the IFI16/STING/IRF3/IFN-β signaling pathway. Additionally, OAd-shp300 induced highly efficient viral replication and potent antitumor activity both in vitro and in vivo. In this study, OAd can reduce p300 expression by promoting its ubiquitination via E1A, thereby enhancing viral replication and cell cytotoxicity. Therefore, this study can provide a biomarker for screening patients who are sensitive to OAd and new ideas for clinical tumor treatment.