Multifaceted HPV16 E2 as a potential therapeutic target for cervical cancer and beyond

Human papillomavirus (HPV) can cause a variety of epithelial lesions, including the malignant proliferation of host cells and even cervical cancer. HPV E2 can play an important role in regulating viral gene expression, viral replication and transcription, and also can participate in the isolation of viral genome during cell division. HPV16 E2 protein is highly expressed in low-differentiated cervical lesion cells, but decreased or disappeared with the increase of cervical lesion grade. As both the initiation protein for DNA replication and the major transcriptional regulator for HPV16 gene expression, E2 protein may play a key role in the viral life cycle. HPV16 E2 protein as a sequence specific DNA binding protein, can bind with the specific DNA recognition sequence on the promoters of E6 and E7 oncogenes, and then inhibit the transcription and expression of E6 and E7 oncogenes, thus inducing cell apoptosis and suppressing tumor formation. Therefore, therapeutic strategies aimed at restoring or enhancing HPV16 E2 function may hold promise for the prevention and treatment of HPV-related cancers, including (i) gene-therapy-mediated E2 restoration; (ii) direct delivery of E2 protein; (iii) E2 stabilization through modulation of interacting pathways (e.g., TopBP1, Brd4); and (iv) E2-based therapeutic vaccines. These approaches may exert antitumor effects by repressing E6/E7 oncogenes, regulating the cell cycle, inhibiting cell proliferation, and inducing apoptosis.