Epigenetic and Genetic Keys to Fight HPV-Related Cancers

Abstract

Cervical cancer ranks as the fourth most prevalent cancer among women globally, with approximately 600,000 new cases being diagnosed each year. The principal driver of cervical cancer is the human papillomavirus (HPV), where viral oncoproteins E6 and E7 undertake the role of driving its carcinogenic potential. Despite extensive investigative efforts, numerous facets concerning HPV infection, replication, and pathogenesis remain shrouded in uncertainty. The virus operates through a variety of epigenetic mechanisms, and the epigenetic signature of HPV-related tumors is a major bottleneck in our understanding of the disease. Recent investigations have unveiled the capacity of viral oncoproteins to influence epigenetic changes within HPV-related tumors, and conversely, these tumors exert an influence on the surrounding epigenetic landscape. Given the escalating occurrence of HPV-triggered tumors and the deficiency of efficacious treatments, substantial challenges emerge. A promising avenue to address this challenge lies in epigenetic modulators. This review aggregates and dissects potential epigenetic modulators capable of combatting HPV-associated infections and diseases. By delving into these modulators, novel avenues for therapeutic interventions against HPV-linked cancers have come to the fore.

Keywords: cancer; combinatorial therapies; epigenetic regulation; human papillomavirus.

Figure 1

HPV features. (A) Structure of the capsid. (B) The genome is represented in a linear fashion with the positions of the viral early (PromAE) and late (PromAL) promoters, early (pAE) and late (pAL) polyadenylation signals; below are the predicted viral ORFs with the positions of the nucleotides in the viral genome. (C) Coding potentials are illustrated for each transcription event; the most abundant transcripts (>60%) are indicated in red, and the less abundant ones are underlined (<5%).

Figure 2

HPV infection, keratinocyte differentiation, and viral protein expression. Pink epithelium layers do not harbor HPVs, while purple host cells are targets for HPV infection.

Figure 3

Integration of HPV into human cells: (A) a single copy of the viral genome integrates; (B) clonal integration event of the viral genome.

Figure 4

HPV genome organization. (A) SDS-polyacrilamide cylindrical gel electrophoresis and gradient slab gel electrophoresis of SDS-dissociated papillomaviruses. Samples included highly purified BPV (a), HPV (b) proteins, and calf liver histones (c); (B) electron microscopy of HPV genomes showed naked HPV DNA molecules (left) and nucleoprotein-DNA complexes (right) [116]. (viral protein 1–11, VP 1–11; H1, histone 1; H2A, histone 2A; H2B, histone 2B; H3, histone 3; H4, and histone 4) [125].