Epigenetic Alterations in Human Papillomavirus-Associated Cancers

Abstract

Approximately 15–20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis.

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers

“…The HPV genome is chromatinized in both its episomal and integrated forms. Viral proteins alter epigenetic regulation of host gene expression to promote viral genome expression (Soto et al 2017). Several chromatin modifiers and transcriptional regulators were recurrently mutated in HPV-positive OSCCs, including histone acetyltransferase EP300, lysine methyltransferases KMT2D and NSD1, the core histone HIST1H2AE, and transcription factors CASZ1, BBX, and TAF5.…”

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

“…These modifications lead to abnormal gene expression in HPVassociated carcinomas by activating oncogenes and transposable elements, which in turn leads to the loss of imprinting or to the inactivation of tumor suppressor genes. 56 Additionally, studies have detected amplification and/or overexpression of the proto-oncogene MYC, localized at 8q24.21, a recognized viral genome insertion site. 6,11,12 Our data revealed increase of MYC copy number in 65% of the tumors, supporting other authors who suggested, that infection may act promoting PeCa establishment by different mechanisms.…”

Could metabolic risk factors contribute to the development of cervical cancer?

“…It has also shown that in 85% of women with HSIL, IGFBP 2 loss expression occurs, which could has clinical utility for monitoring patients with a higher risk of CxCa progression [39]. Some epigenetic mechanisms have been described in CxCa, related to the effects of HPV on viral and host genome [40,41]. Some of them involve the components of the IGF system, such as IGF2 loss of imprinting, which can lead to some genes overexpression and overall chromatin instability [42] and E7 interaction with a group of lncRNA that modulate PI3K/Akt/mTOR and Wnt- catenin pathways in cervical carcinogenesis process [43].…”