Epigenetic and Transcriptomic Regulation Landscape in HPV+ Cancers: Biological and Clinical Implications

Abstract

Human Papillomavirus (HPV) is an oncogenic virus that causes the highest number of viral-associated cancer cases and deaths worldwide, with more than 690,000 new cases per year and 342,000 deaths only for cervical cancer (CC). Although the incidence and mortality rates for CC are declining in countries where screening and vaccination programs have been implemented, other types of cancer in which HPV is involved, such as oropharyngeal cancer, are increasing, particularly in men. Mutational and transcriptional profiles of various HPV-associated neoplasms have been described, and accumulated evidence has shown the oncogenic capacity of E6, E7, and E5 genes of high-risk HPV. Interestingly, transcriptomic analysis has revealed that although a vast majority of the human genome is transcribed into RNAs, only 2% of transcripts are translated into proteins. The remaining transcripts lacking protein-coding potential are called non-coding RNAs. In addition to the transfer and ribosomal RNAs, there are regulatory non-coding RNAs classified according to size and structure in long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small RNAs; such as microRNAs (miRNAs), piwi-associated RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and endogenous short-interfering RNAs. Recent evidence has shown that lncRNAs, miRNAs, and circRNAs are aberrantly expressed under pathological conditions such as cancer. In addition, those transcripts are dysregulated in HPV-related neoplasms, and their expression correlates with tumor progression, metastasis, poor prognosis, and recurrence. Nuclear lncRNAs are epigenetic regulators involved in controlling gene expression at the transcriptional level through chromatin modification and remodeling. Moreover, disruption of the expression profiles of those lncRNAs affects multiple biological processes such as cell proliferation, apoptosis, and migration. This review highlights the epigenetic alterations induced by HPV, from infection to neoplastic transformation. We condense the epigenetic role of non-coding RNA alterations and their potential as biomarkers in transformation's early stages and clinical applications. We also summarize the molecular mechanisms of action of nuclear lncRNAs to understand better their role in the epigenetic control of gene expression and how they can drive the malignant phenotype of HPV-related neoplasia. Finally, we review several chemical and epigenetic therapy options to prevent and treat HPV-associated neoplasms.

Keywords: HPV; LncRNA; biomarker; epigenetic; miRNA; regulation; therapy; viral oncoprotein.

FIGURE 1

HPV-attributable cancer. (A) The graph shows the proportion of cancer attributable to HPV worldwide (B) Number of new cancer cases attributable to HPV. Data from de Martel et al. (2020).

FIGURE 2

HPV Chromatin. The figure illustrates the HPV chromatin regulation. The inner-circle indicates the distribution of the viral genes. The tags indicate the position of the corresponding chromatin mark. In addition, the characteristic loop between CTCF and the LCR region is illustrated. See text for more detail.

FIGURE 3

Changes of methylation in LCR of HPV 16. (A) LCR region binding sites. (B) Schematic illustrating LCR methylation changes of HPV 16 isolated from different epithelial layers. The letters “S,” “I,” and “B” refer to superficial, intermediate, and basal layers respectively, and at different stages of viral infection and transformation. Dark spots show methylated CpG clear spots show unmethylated CpG. Data from Vinokurova and von Knebel Doeberitz 2011, Chaiwongkot et al. (2013).

FIGURE 4

HPV-encoded miRNAs. (A) Illustration shows the miRNAs coding site inside the genome of different HPV subtypes. The predicted biological processes for some HPV16 miRNAs are depicted in the figure. The circE7 synthesis site is also shown. (B) The scheme represents the potential interaction sites of miRNAs in the viral genome of HPV-16 and HPV-41. The predicted target viral sequences location for each miRNA are shown in the same color as the corresponding miRNA sequence (blue, red, or purple).

FIGURE 5

lncRNAs regulated by E6/E7 oncoproteins. The figure shows the molecular mechanisms of lncRNAs regulated by the E6/E7 oncoproteins. Blue circles refer to oncogenic lncRNAs and red circles to tumor suppressors.