Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications

Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.     

Inhibition or Reversal of the Epithelial-Mesenchymal Transition in Gastric Cancer: Pharmacological Approaches

Epithelial-mesenchymal transition (EMT) constitutes one of the hallmarks of carcinogenesis consisting in the re-differentiation of the epithelial cells into mesenchymal ones changing the cellular phenotype into a malignant one. EMT has been shown to play a role in the malignant transformation and while occurring in the tumor microenvironment, it significantly affects the aggressiveness of gastric cancer, among others. Importantly, after EMT occurs, gastric cancer patients are more susceptible to the induction of resistance to various therapeutic agents, worsening the clinical outcome of patients. Therefore, there is an urgent need to search for the newest pharmacological agents targeting EMT to prevent further progression of gastric carcinogenesis and potential metastases. Therapies targeted at EMT might be combined with other currently available treatment modalities, which seems to be an effective strategy to treat gastric cancer patients. In this review, we have summarized recent advances in gastric cancer treatment in terms of targeting EMT specifically, such as the administration of polyphenols, resveratrol, tangeretin, luteolin, genistein, proton pump inhibitors, terpenes, other plant extracts, or inorganic compounds.     

MicroRNA Methylome Signature and Their Functional Roles in Colorectal Cancer Diagnosis,Prognosis, and Chemoresistance

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite significant advances in the diagnostic services and patient care, several gaps remain to be addressed, from early detection, to identifying prognostic variables, effective treatment for the metastatic disease, and the implementation of tailored treatment strategies. MicroRNAs, the short non-coding RNA species, are deregulated in CRC and play a significant role in the occurrence and progression. Nevertheless, microRNA research has historically been based on expression levels to determine its biological significance. The exact mechanism underpinning microRNA deregulation in cancer has yet to be elucidated, but several studies have demonstrated that epigenetic mechanisms play important roles in the regulation of microRNA expression, particularly DNA methylation. However, the methylation profiles of microRNAs remain unknown in CRC patients. Methylation is the next major paradigm shift in cancer detection since large-scale epigenetic alterations are potentially better in identifying and classifying cancers at an earlier stage than somatic mutations. This review aims to provide insight into the current state of understanding of microRNA methylation in CRC. The new knowledge from this study can be utilized for personalized health diagnostics, disease prediction, and monitoring of treatment.     

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.     

Plant DNA Methylation: An Epigenetic Mark in Development,Environmental Interactions,and Evolution

DNA methylation is an epigenetic modification of the genome involved in the regulation of gene expression and modulation of chromatin structure. Plant genomes are widely methylated, and the methylation generally occurs on the cytosine bases through the activity of specific enzymes called DNA methyltransferases. On the other hand, methylated DNA can also undergo demethylation through the action of demethylases. The methylation landscape is finely tuned and assumes a pivotal role in plant development and evolution. This review illustrates different molecular aspects of DNA methylation and some plant physiological processes influenced by this epigenetic modification in model species, crops, and ornamental plants such as orchids. In addition, this review aims to describe the relationship between the changes in plant DNA methylation levels and the response to biotic and abiotic stress. Finally, we discuss the possible evolutionary implications and biotechnological applications of DNA methylation.     

Mechanisms and Αpplications of Ιnterleukins in Cancer Immunotherapy

Over the past years, advances in cancer immunotherapy have resulted in innovative and novel approaches in molecular cancer diagnostics and cancer therapeutic procedures. However, due to tumor heterogeneity and inter-tumoral discrepancy in tumor immunity, the clinical benefits are quite restricted. The goal of this review is to evaluate the major cytokines-interleukins involved in cancer immunotherapy and project their basic biochemical and clinical applications. Emphasis will be given to new cytokines in pre-clinical development, and potential directions for future investigation using cytokines. Furthermore, current interleukin-based approaches and clinical trial data from combination cancer immunotherapies will also be discussed. It appears that continuously increasing comprehension of cytokine-induced effects, cancer stemness, immunoediting, immune-surveillance as well as understanding of molecular interactions emerging in the tumor microenvironment and involving microRNAs, autophagy, epithelial-mesenchymal transition (EMT), inflammation, and DNA methylation processes may hold much promise in improving anti-tumor immunity. To this end, the emerging in-depth knowledge supports further studies on optimal synergistic combinations and additional adjuvant therapies to realize the full potential of cytokines as immunotherapeutic agents.     

Epigenetic Regulation of microRNAs in Cancer: Shortening the Distance from Bench to Bedside

Cancer is a complex disease involving alterations of multiple processes, with both genetic and epigenetic features contributing as core factors to the disease. In recent years, it has become evident that non-coding RNAs (ncRNAs), an epigenetic factor, play a key role in the initiation and progression of cancer. MicroRNAs, the most studied non-coding RNAs subtype, are key controllers in a myriad of cellular processes, including proliferation, differentiation, and apoptosis. Furthermore, the expression of miRNAs is controlled, concomitantly, by other epigenetic factors, such as DNA methylation and histone modifications, resulting in aberrant patterns of expression upon the occurrence of cancer. In this sense, aberrant miRNA landscape evaluation has emerged as a promising strategy for cancer management. In this review, we have focused on the regulation (biogenesis, processing, and dysregulation) of miRNAs and their role as modulators of the epigenetic machinery. We have also highlighted their potential clinical value, such as validated diagnostic and prognostic biomarkers, and their relevant role as chromatin modifiers in cancer therapy.     

Long Noncoding RNA GAS5 in Breast Cancer: Epigenetic Mechanisms and Biological Functions

Long noncoding RNAs (lncRNAs) have been identified as contributors to the development and progression of cancer through various functions and mechanisms. LncRNA GAS5 is downregulated in multiple cancers and acts as a tumor suppressor in breast cancer. GAS5 interacts with various proteins (e.g., E2F1, EZH2, and YAP), DNA (e.g., the insulin receptor promoter), and various microRNAs (miRNAs). In breast cancer, GAS5 binds with miR-21, miR-222, miR-221-3p, miR-196a-5p, and miR-378a-5p that indicates the presence of several elements for miRNA binding (MREs) in GAS5. Mediated by the listed miRNAs, GAS5 is involved in the upregulation of a number of mRNAs of suppressor proteins such as PTEN, PDCD4, DKK2, FOXO1, and SUFU. Furthermore, the aberrant promoter methylation is involved in the regulation of GAS5 gene expression in triple-negative breast cancer and some other carcinomas. GAS5 can stimulate apoptosis in breast cancer via diverse pathways, including cell death receptors and mitochondrial signaling pathways. GAS5 is also a key player in the regulation of some crucial signal pathways in breast cancer, such as PI3K/AKT/mTOR, Wnt/β-catenin, and NF-κB signaling. Through epigenetic and other mechanisms, GAS5 can increase sensitivity to multiple drugs and improve prognosis. GAS5 is thus a promising target in the treatment of breast cancer patients.     

Role of miRNA in Melanoma Development and Progression

Melanoma is one of the most aggressive and progressive skin cancers. It develops from normal pigment-producing cells known as melanocytes, so it is important to know the mechanism behind such transformations. The study of metastasis mechanisms is crucial for a better understanding the biology of neoplastic cells. Metastasis of melanoma, or any type of cancer, is a multi-stage process in which the neoplastic cells leave the primary tumour, travel through the blood and/or lymphatic vessels, settle in distant organs and create secondary tumours. MicroRNA (miRNA) can participate in several steps of the metastatic process. This review presents the role of miRNA molecules in the development and progression as well as the immune response to melanoma.     

Cripto-1 as a Key Factor in Tumor Progression,Epithelial to Mesenchymal Transition and Cancer Stem Cells

Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1’s role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients.     

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.     

Epigenetic Aging and Colorectal Cancer: State of the Art and Perspectives for Future Research

Although translational research has identified a large number of potential biomarkers involved in colorectal cancer (CRC) carcinogenesis, a better understanding of the molecular pathways associated with biological aging in colorectal cells and tissues is needed. Here, we aim to summarize the state of the art about the role of age acceleration, defined as the difference between epigenetic age and chronological age, in the development and progression of CRC. Some studies have shown that accelerated biological aging is positively associated with the risk of cancer and death in general. In line with these findings, other studies have shown how the assessment of epigenetic age in people at risk for CRC could be helpful for monitoring the molecular response to preventive interventions. Moreover, it would be interesting to investigate whether aberrant epigenetic aging could help identify CRC patients with a high risk of recurrence and a worst prognosis, as well as those who respond poorly to treatment. Yet, the application of this novel concept is still in its infancy, and further research should be encouraged in anticipation of future applications in clinical practice.     

Epigenetic Dysregulations in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma

Merkel cell polyomavirus (MCPyV) is a small DNA virus with oncogenic potential. MCPyV is the causative agent of Merkel Cell Carcinoma (MCC), a rare but aggressive tumor of the skin. The role of epigenetic mechanisms, such as histone posttranslational modifications (HPTMs), DNA methylation, and microRNA (miRNA) regulation on MCPyV-driven MCC has recently been highlighted. In this review, we aim to describe and discuss the latest insights into HPTMs, DNA methylation, and miRNA regulation, as well as their regulative factors in the context of MCPyV-driven MCC, to provide an overview of current findings on how MCPyV is involved in the dysregulation of these epigenetic processes. The current state of the art is also described as far as potentially using epigenetic dysregulations and related factors as diagnostic and prognostic tools is concerned, in addition to targets for MCPyV-driven MCC therapy. Growing evidence suggests that the dysregulation of HPTMs, DNA methylation, and miRNA pathways plays a role in MCPyV-driven MCC etiopathogenesis, which, therefore, may potentially be clinically significant for this deadly tumor. A deeper understanding of these mechanisms and related factors may improve diagnosis, prognosis, and therapy for MCPyV-driven MCC.