Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

Abstract

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…In vitro and in vivo studies have demonstrated that HDAC inhibitors, such as the FDA approved drugs vorinostat, belinostat and panobinostat, could be a promising therapy for HPV-positive cancers [ 378 ]. A phase I/II study with the HDAC inhibitor entinostat is now recruiting patients with HPV associated malignancies (clinical trial study NCT04708470).…”

The Involvement of Natural Polyphenols in the Chemoprevention of Cervical Cancer

“…Dietary polyphenols can modulate histone modification to prevent cancer by inhibiting HDAC [4,51]. Quercetin (inhibits HDAC2, HDAC4, HDAC7, and HDAC8), genistein (inhibits HDAC6 and tyrosine kinases), caffeic acid, and curcumin are the most well known for their capacity of inhibiting HDACs (Figure 6) [58]. Non-Coding RNA: MicroRNA MicroRNAs (miRNAs) are short, non-coding single-stranded RNA fragments that regulate cellular processes through transcriptional repression and degradation of messenger RNA (mRNA) [59].…”

Epigenetic Dysregulations in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma

“…Epigenetic altering factors include oncogenic viruses, such as high-risk human papillomaviruses (HR-HPVs), Epstein–Barr virus, Hepatitis viruses, and Kaposi’s sarcoma-associated herpesvirus [ 17 , 18 , 19 ]. These viruses have been found to be associated with epigenetic dysregulations in different tumors [ 20 , 21 , 22 ], whereas their oncoproteins have been shown to induce dysfunctions in proteins/enzymes involved in controlling DNA methylation, chromatin modification, and miRNA expression [ 17 , 18 , 23 ].…”

“…These viruses have been found to be associated with epigenetic dysregulations in different tumors [ 20 , 21 , 22 ], whereas their oncoproteins have been shown to induce dysfunctions in proteins/enzymes involved in controlling DNA methylation, chromatin modification, and miRNA expression [ 17 , 18 , 23 ]. Notably, epigenetic dysregulations have been shown to function as potential diagnostic and prognostic biomarkers as well as therapeutic targets in different virus-driven cancers [ 19 , 21 ].…”