Pathogen-Induced Epigenetic Modifications in Cancers: Implications for Prevention, Detection and Treatment of Cancers in Africa

Cancer is a major public health burden worldwide. Tumor formation is caused by multiple intrinsic and extrinsic factors. Many reports have demonstrated a positive correlation between the burden of infectious pathogens and the occurrence of cancers. However, the mechanistic link between pathogens and cancer development remains largely unclear and is subject to active investigations. Apart from somatic mutations that have been widely linked with various cancers, an appreciable body of knowledge points to alterations of host epigenetic patterns as key triggers for cancer development. Several studies have associated various infectious pathogens with epigenetic modifications. It is therefore plausible to assume that pathogens induce carcinogenesis via alteration of normal host epigenetic patterns. Thus, Africa with its disproportionate burden of infectious pathogens is threatened by a dramatic increase in pathogen-mediated cancers. To curb the potential upsurge of such cancers, a better understanding of the role of tropical pathogens in cancer epigenetics could substantially provide resources to improve cancer management among Africans. Therefore, this review discusses cancer epigenetic studies in Africa and the link between tropical pathogens and cancer burden. In addition, we discuss the potential mechanisms by which pathogens induce cancers and the opportunities and challenges of tropical pathogen-induced epigenetic changes for cancer prevention, detection and management.

O-GlcNAcylation links oncogenic signals and cancer epigenetics

Prevalent dysregulation of epigenetic modifications plays a pivotal role in cancer. Targeting epigenetic abnormality is a new strategy for cancer therapy. Understanding how conventional oncogenic factors cause epigenetic abnormality is of great basic and translational value. O-GlcNAcylation is a protein modification which affects physiology and pathophysiology. In mammals, O-GlcNAcylation is catalyzed by one single enzyme OGT and removed by one single enzyme OGA. O-GlcNAcylation is affected by the availability of the donor, UDP-GlcNAc, generated by the serial enzymatic reactions in the hexoamine biogenesis pathway (HBP). O-GlcNAcylation regulates a wide spectrum of substrates including many proteins involved in epigenetic modification. Like epigenetic modifications, abnormality of O-GlcNAcylation is also common in cancer. Studies have revealed substantial impact on HBP enzymes and OGT/OGA by oncogenic signals. In this review, we will first summarize how oncogenic signals regulate HBP enzymes, OGT and OGA in cancer. We will then integrate this knowledge with the up to date understanding how O-GlcNAcylation regulates epigenetic machinery. With this, we propose a signal axis from oncogenic signals through O-GlcNAcylation dysregulation to epigenetic abnormality in cancer. Further elucidation of this axis will not only advance our understanding of cancer biology but also provide new revenues towards cancer therapy.

AN OVERVIEW OF EPIGENETIC DRUGS, AND THEIR VIRTUAL SCREENING STUDY RETRIEVED FROM ZINC DATABASE ALONG WITH AN AUTODOCK STUDY OF THE BEST INHIBITOR

Objective: Over the last 30 y cancer epigenetics research has grown extensively. It is note-worthy to recognize that epigenetic misregulation could substantiate the development of cancer and we need to continue to look for anti-neoplastic epi-drugs. Taking into consideration this phenomenon, our first aim is to search for an effective epi-drugs by virtual screening from ZINC database and to explore the validity of the virtual screening. The second aim is to explore a binding conformation of the top affinity ligands against macromolecules, by docking experiment. Methods: The virtual screening was conducted by our Virtual Screening by Docking (VSDK) algorithm and procedure. Small molecules were randomly downloaded by ZINC database. For docking experiment, AutoDock 4.2.6 and AutoDock Tool were used. Results: It took eight to ten hours for the successful virtual screening of the 2778 small compounds retrieved at random from ZINC database. Among histone H2B E76K mutant (HHEM) inhibitors and DNA methyltransferase (DNMT) inhibitors, the first ranked inhibitors were 1H-1,2,4-triazole-3,5-diamine and 2-ethyl-1,3,4-oxadiazole respectively. Conclusion: As for the molecular structures obtained from virtual screening, most of the top ten HHEM and DNMT inhibitors contained 5-member rings. More than two times in affinity difference between the top and bottom ten compounds would indicate a successful virtual screening experiment. The histogram chart of AutoDock4 runs appeared in the lowest affinity region with two or three hydrogen bonds indicating a reliable conformation docking.

Ovarian cancer: epigenetics, drug resistance, and progression

Ovarian cancer (OC) is one of the most common malignant tumors in women. OC is associated with the activation of oncogenes, the inactivation of tumor suppressor genes, and the activation of abnormal cell signaling pathways. Moreover, epigenetic processes have been found to play an important role in OC tumorigenesis. Epigenetic processes do not change DNA sequences but regulate gene expression through DNA methylation, histone modification, and non-coding RNA. This review comprehensively considers the importance of epigenetics in OC, with a focus on microRNA and long non-coding RNA. These types of RNA are promising molecular markers and therapeutic targets that may support precision medicine in OC. DNA methylation inhibitors and histone deacetylase inhibitors may be useful for such targeting, with a possible novel approach combining these two therapies. Currently, the clinical application of such epigenetic approaches is limited by multiple obstacles, including the heterogeneity of OC, insufficient sample sizes in reported studies, and non-optimized methods for detecting potential tumor markers. Nonetheless, the application of epigenetic approaches to OC patient diagnosis, treatment, and prognosis is a promising area for future clinical investigation.

An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality

Although cancer is traditionally considered a genetic disease, the epigenetic abnormalities, including DNA hypermethylation, histone deacetylation, and/or microRNA dysregulation, have been demonstrated as a hallmark of cancer. Compared with gene mutations, aberrant epigenetic changes occur more frequently, and cellular epigenome is more susceptible to change by environmental factors. Excess cancer risks are positively associated with exposure to occupational and environmental chemical carcinogens, including those from gasoline combustion exhausted in vehicles. Of note, previous studies proposed particulate matter index (PMI) as a measure for gasoline sooting tendency, and showed that, compared with the other molecules in gasoline, 1,2,4–Trimethylbenzene, 2–methylnaphthalene and toluene significantly contribute to PMI of the gasoline blends. Mechanistically, both epigenome and genome are important in carcinogenicity, and the genotoxicity of chemical agents has been thoroughly studied. However, less effort has been put into studying the epigenotoxicity. Moreover, as the blending of ethanol into gasoline substitutes for carcinogens, like benzene, toluene, xylene, butadiene, and polycyclic aromatic hydrocarbons, etc., a reduction of secondary aromatics has been achieved in the atmosphere. This may lead to diminished cancer initiation and progression through altered cellular epigenetic landscape. The present review summarizes the most important findings in the literature on the association between exposures to carcinogens from gasoline combustion, cancer epigenetics and the potential epigenetic impacts of biofuels.

Remodeling the Epigenetic Landscape of Cancer—Application Potential of Flavonoids in the Prevention and Treatment of Cancer

Epigenetics, including DNA methylation, histone modification, and noncoding RNA regulation, are physiological regulatory changes that affect gene expression without modifying the DNA sequence. Although epigenetic disorders are considered a sign of cell carcinogenesis and malignant events that affect tumor progression and drug resistance, in view of the reversible nature of epigenetic modifications, clinicians believe that associated mechanisms can be a key target for cancer prevention and treatment. In contrast, epidemiological and preclinical studies indicated that the epigenome is constantly reprogrammed by intake of natural organic compounds and the environment, suggesting the possibility of utilizing natural compounds to influence epigenetics in cancer therapy. Flavonoids, although not synthesized in the human body, can be consumed daily and are common in medicinal plants, vegetables, fruits, and tea. Recently, numerous reports provided evidence for the regulation of cancer epigenetics by flavonoids. Considering their origin in natural and food sources, few side effects, and remarkable biological activity, the epigenetic antitumor effects of flavonoids warrant further investigation. In this article, we summarized and analyzed the multi-dimensional epigenetic effects of all 6 subtypes of flavonoids (including flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanidin) in different cancer types. Additionally, our report also provides new insights and a promising direction for future research and development of flavonoids in tumor prevention and treatment via epigenetic modification, in order to realize their potential as cancer therapeutic agents.

Histone H2B Mutations in Cancer

Oncohistones have emerged as a new area in cancer epigenetics research. Recent efforts to catalogue histone mutations in cancer patients have revealed thousands of histone mutations across different types of cancer. In contrast to previously identified oncohistones (H3K27M, H3G34V/R, and H3K36M), where the mutations occur on the tail domain and affect histone post-translational modifications, the majority of the newly identified mutations are located within the histone fold domain and affect gene expression via distinct mechanisms. The recent characterization of the selected H2B has revealed previously unappreciated roles of oncohistones in nucleosome stability, chromatin accessibility, and chromatin remodeling. This review summarizes recent advances in the study of H2B oncohistones and other emerging oncohistones occurring on other types of histones, particularly those occurring on the histone fold domain.

The dark side of histones: genomic organization and role of oncohistones in cancer

Background The oncogenic role of histone mutations is one of the most relevant discovery in cancer epigenetics. Recurrent mutations targeting histone genes have been described in pediatric brain tumors, chondroblastoma, giant cell tumor of bone and other tumor types. The demonstration that mutant histones can be oncogenic and drive the tumorigenesis in pediatric tumors, led to the coining of the term “oncohistones.” The first identified histone mutations were localized at or near residues normally targeted by post-translational modifications (PTMs) in the histone N-terminal tails and suggested a possible interference with histone PTMs regulation and reading. Main body In this review, we describe the peculiar organization of the multiple genes that encode histone proteins, and the latter advances in both the identification and the biological role of histone mutations in cancer. Recent works show that recurrent somatic mutations target both N-terminal tails and globular histone fold domain in diverse tumor types. Oncohistones are often dominant-negative and occur at higher frequencies in tumors affecting children and adolescents. Notably, in many cases the mutations target selectively only some of the genes coding the same histone protein and are frequently associated with specific tumor types or, as documented for histone variant H3.3 in pediatric glioma, with peculiar tumors arising from specific anatomic locations. Conclusion The overview of the most recent advances suggests that the oncogenic potential of histone mutations can be exerted, together with the alteration of histone PTMs, through the destabilization of nucleosome and DNA–nucleosome interactions, as well as through the disruption of higher-order chromatin structure. However, further studies are necessary to fully elucidate the mechanism of action of oncohistones, as well as to evaluate their possible application to cancer classification, prognosis and to the identification of new therapies.

Identifying Differential Methylation in Cancer Epigenetics via a Bayesian Functional Regression Model

DNA methylation plays an essential role in regulating gene activity, modulating disease risk, and determining treatment response. Researchers can obtain insight into methylation patterns at a single nucleotide level utilizing next-generation sequencing technologies. However, complex features inherent in the data obtained via these technologies pose challenges beyond the typical big data problems. Identifying differentially methylated cytosines (dmc) or regions is one of such challenges. Current methodologies for identifying dmcs fall short in handling low read-depth data and missing values, capturing functional data patterns, granting multiple covariates (categorical, continuous, or combination), and multiple group comparisons. We have developed an efficient method to identify dmcs based on a Bayesian functional regression approach, termed DMCFB, that tackles these shortcomings. Through simulation studies, we establish that DMCFB outperforms current methods and results in better smoothing, and efficient imputation. We apply the proposed method to analyze a dataset containing patients with acute promyelocytic leukemia and control samples. With DMCFB, we discovered many new dmcs, and more importantly, exhibited enhanced consistency of differential methylation within islands and at their adjacent shores. Furthermore, we detected differential methylation at more of the binding sites of the fused gene involved in this cancer.