Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

Colon and rectal cancer (colorectal cancer, CRC) is the third most common cancer worldwide. Deaths from CRC account for around 8% of all cancer deaths, making it the fourth most common cause of death from cancer. The high mortality rate of colon cancer is mainly attributable to its metastasis. Efforts have been made to identify metastasis suppressor genes, which encode proteins responsible for inhibiting the metastasis but not suppressing the growth of primary tumors. Studies on metastasis suppressor genes demonstrated that epigenetic modifications, such as DNA promoter methylation and histone modification, play crucial roles in regulating the expression of many metastasis suppressor genes, which indicates the association between aberrant epigenetic alterations and cancer metastasis. This review will focus on the recent findings regarding metastasis suppressors regulated by epigenetic modifications, particularly DNA methylation and histone modification, in CRC metastasis. Also discussed will be recent progress on the suppression of CRC metastasis by genistein, a soy isoflavone, with a focus on epigenetic mechanisms.     

Histone modifications as a pathogenic mechanism of colorectal tumorigenesis

Epigenetic regulation of gene expression has provided colorectal cancer (CRC) pathogenesis with an additional trait during the past decade. In particular, histone post-translational modifications set up a major component of this process dictating chromatin status and recruiting non-histone proteins in complexes formed to "handle DNA". In CRC, histone marks of aberrant acetylation and methylation levels on specific residues have been revealed, along with a plethora of deregulated enzymes that catalyze these reactions. Mutations, deletions or altered expression patterns transform the function of several histone-modifying proteins, further supporting the crucial role of epigenetic effectors in CRC oncogenesis, being closely associated to inactivation of tumor suppressor genes. Elucidation of the biochemical basis of these new tumorigenic mechanisms allows novel potential prognostic factors to come into play. Moreover, the detection of these changes even in early stages of the multistep CRC process, along with the reversible nature of these mechanisms and the technical capability to detect such alterations in cancer cells, places this group of covalent modifications as a further potential asset for clinical diagnosis or treatment of CRC. This review underlines the biochemistry of histone modifications and the potential regulatory role of histone-modifying proteins in CRC pathogenesis, to date. Furthermore, the underlying mechanisms of the emerging epigenetic interplay along with the chemical compounds that are candidates for clinical use are discussed, offering new insights for further investigation of key histone enzymes and new therapeutic targets.     

Epigenetics Alterations in Preneoplastic and Neoplastic Lesions of the Cervix

ABSTRACT: Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations.     

Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications

In the last three decades huge efforts have been made to characterize genetic defects responsible for cancer development and progression, leading to the comprehensive identification of distinct cellular pathways affected by the alteration of specific genes. Despite the undoubtable role of genetic mechanisms in triggering neoplastic cell transformation, epigenetic modifications (i.e., heritable changes of gene expression that do not derive from alterations of the nucleotide sequence of DNA) are rapidly emerging as frequent alterations that often occur in the early phases of tumorigenesis and that play an important role in tumor development and progression. Epigenetic alterations, such as modifications in DNA methylation patterns and post-translational modifications of histone tails, behave extremely different from genetic modifications, being readily revertable by "epigenetic drugs" such as inhibitors of DNA methyl transferases and inhibitors of histone deacetylases. Since epigenetic alterations in cancer cells affect virtually all cellular pathways that have been associated to tumorigenesis, it is not surprising that epigenetic drugs display pleiotropic activities, being able to concomitantly restore the defective expression of genes involved in cell cycle control, apoptosis, cell signaling, tumor cell invasion and metastasis, angiogenesis and immune recognition. Prompted by this emerging clinical relevance of epigenetic drugs, this review will focus on the large amount of available data, deriving both from in vitro experimentations and in vivo pre-clinical and clinical studies, which clearly indicate epigenetic drugs as effective modifiers of cancer phenotype and as positive regulators of tumor cell biology with a relevant therapeutic potential in cancer patients.     

Epigenetic modifications in rheumatoid arthritis

Over the last decades, genetic factors for rheumatoid diseases like the HLA haplotypes have been studied extensively. However, during the past years of research, it has become more and more evident that the influence of epigenetic processes on the development of rheumatic diseases is probably as strong as the genetic background of a patient. Epigenetic processes are heritable changes in gene expression without alteration of the nucleotide sequence. Such modifications include chromatin methylation and post-translational modification of histones or other chromatin-associated proteins. The latter comprise the addition of methyl, acetyl, and phosphoryl groups or even larger moieties such as binding of ubiquitin or small ubiquitin-like modifier. The combinatory nature of these processes forms a complex network of epigenetic modifications that regulate gene expression through activation or silencing of genes. This review provides insight into the role of epigenetic alterations in the pathogenesis of rheumatoid arthritis and points out how a better understanding of such mechanisms may lead to novel therapeutic strategies.     

Involvement of aberrant regulation of epigenetic mechanisms in the pathogenesis of Parkinson's disease and epigenetic-based therapies

Parkinson's disease (PD) is known as a progressive neurodegenerative disorder associated with the reduction of dopamine-secreting neurons and the formation of Lewy bodies in the substantia nigra and basal ganglia routes. Aging, as well as environmental and genetic factors, are considered as disease risk factors that can make PD as a complex one. Epigenetics means studying heritable changes in gene expression or function, without altering the underlying DNA sequence. Multiple studies have shown the association of epigenetic variations with onset or progression of various types of diseases. DNA methylation, posttranslational modifications of histones and presence of microRNA (miRNA) are among epigenetic processes involved in regulating pathways related to the development of PD. Unlike genetic mutations, most epigenetic variations may be reversible or preventable. Therefore, the return of aberrant epigenetic events in different cells is a growing therapeutic approach to treatment or prevention. Currently, there are several methods for treating PD patients, the most important of which are drug therapies. However, detection of genes and epigenetic mechanisms involved in the disease can develop appropriate diagnosis and treatment of the disease before the onset of disabilities and resulting complications. The main purpose of this study was to review the most important epigenetic molecular mechanisms, epigenetic variations in PD, and epigenetic-based therapies.     

Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer

Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and –II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained.     

Epigenetic therapy of leukemia: An update

Carcinogenesis is classically thought to result from genetic alterations in DNA sequence such as deletions, mutations, or chromosomal translocations. These in turn may lead to the activation of oncogenes, inactivation of tumor suppressor genes or formation of chimeric oncoproteins. Epigenetics, in contrast, refers to a number of biochemical modifications of chromatin, either to DNA directly or to its associated protein complexes that affect gene expression without altering the primary sequence of DNA [Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11-9; Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-92]. A fundamental difference between genetic and epigenetic alterations is the irreversible nature of genetic lesions whereas epigenetic ones are potentially reversible, allowing for therapeutic intervention. In the last decade, it has become apparent that epigenetic changes play an important role in cancer, particularly in leukemia. Significant advances have been made in the elucidation of these processes as well as in translating this knowledge to the clinic, as in the development of new prognostic biomarkers or targeted therapies. In this review, we will focus on recent advances in epigenetic therapy in leukemia.     

DNA甲基化对子宫内膜异位症(EMs)的作用及其调控机制

表观遗传通过DNA甲基化、组蛋白修饰、染色质重塑、以及microRNA等调控方式来实现对基因表达、DNA复制和基因组稳定性的控制。DNA甲基化是目前研究的最为广泛的表观遗传修饰方式之一,可调控真核生物的基因表达。DNA甲基化在哺乳动物发育、肿瘤发生发展及人类其他疾病中均发挥着至关重要的作用。DNA甲基化状态的改变已被视为人类肿瘤细胞的生物标志之一。EMs虽是一种良性妇科疾病,但伴有细胞增殖、侵袭性及远处种植转移等肿瘤的特点。最新研究发现,DNA甲基化可能与子宫内膜异位症(EMs)的发生存在密切的关系并认为EMs从根本上是一种表观遗传学疾病。由于表观遗传修饰都是可逆的过程,这就为EMs的治疗提供了一种新的途径。本文就DNA甲基化在EMs中的发生发展中的作用及其调控的分子机制,以及在诊断治疗中作用的最新研究进展做一综述。     

DNA甲基化对子宫内膜异位症（EMs）的作用及其调控机制

表观遗传通过DNA甲基化、组蛋白修饰、染色质重塑、以及microRNA等调控方式来实现对基因表达、DNA复制和基因组稳定性的控制。DNA甲基化是目前研究的最为广泛的表观遗传修饰方式之一,可调控真核生物的基因表达。DNA甲基化在哺乳动物发育、肿瘤发生发展及人类其他疾病中均发挥着至关重要的作用。DNA甲基化状态的改变已被视为人类肿瘤细胞的生物标志之一。EMs虽是一种良性妇科疾病,但伴有细胞增殖、侵袭性及远处种植转移等肿瘤的特点。最新研究发现,DNA甲基化可能与子宫内膜异位症（EMs）的发生存在密切的关系并认为EMs从根本上是一种表观遗传学疾病。由于表观遗传修饰都是可逆的过程,这就为EMs的治疗提供了一种新的途径。本文就DNA甲基化在EMs中的发生发展中的作用及其调控的分子机制,以及在诊断治疗中作用的最新研究进展做一综述。     

Epigenetic events in malignant melanoma

Irreversible changes in the DNA sequence, including chromosomal deletions or amplification, activating or inactivating mutations in genes, have been implicated in the development and progression of melanoma. However, increasing attention is being turned towards the participation of 'epigenetic' events in melanoma progression that do not affect DNA sequence, but which nevertheless may lead to stable inherited changes in gene expression. Epigenetic events including histone modifications and DNA methylation play a key role in normal development and are crucial to establishing the correct program of gene expression. In contrast, mistargeting of such epigenetic modifications can lead to aberrant patterns of gene expression and loss of anti-cancer checkpoints. Thus, to date at least 50 genes have been reported to be dysregulated in melanoma by aberrant DNA methylation and accumulating evidence also suggests that mistargetting of histone modifications and altered chromatin remodeling activities will play a key role in melanoma. This review gives an overview of the many different types of epigenetic modifications and their involvement in cancer and especially in melanoma development and progression.     

Dynamic regulation of DNA methylation and histone modifications in response to abiotic stresses in plants

DNA methylation and histone modification are evolutionarily conserved epigenetic modifications that are crucial for the expression regulation of abiotic stress-responsive genes in plants. Dynamic changes in gene expression levels can result from changes in DNA methylation and histone modifications. In the last two decades, how epigenetic machinery regulates abiotic stress responses in plants has been extensively studied. Here, based on recent publications, we review how DNA methylation and histone modifications impact gene expression regulation in response to abiotic stresses such as drought, abscisic acid, high salt, extreme temperature, nutrient deficiency or toxicity, and ultraviolet B exposure. We also review the roles of epigenetic mechanisms in the formation of transgenerational stress memory. We posit that a better understanding of the epigenetic underpinnings of abiotic stress responses in plants may facilitate the design of more stress-resistant or -resilient crops, which is essential for coping with global warming and extreme environments.     

Epigenetic modifications of histones during osteoblast differentiation

In bone biology, epigenetics plays a key role in mesenchymal stem cells' (MSCs) commitment towards osteoblasts. It involves gene regulatory mechanisms governed by chromatin modulators. Predominant epigenetic mechanisms for efficient osteogenic differentiation include DNA methylation, histone modifications, and non-coding RNAs. Among these mechanisms, histone modifications critically contribute to altering chromatin configuration. Histone based epigenetic mechanisms are an essential mediator of gene expression during osteoblast differentiation as it directs the bivalency of the genome. Investigating the importance of histone modifications in osteogenesis may lead to the development of epigenetic-based remedies for genetic disorders of bone. Hence, in this review, we have highlighted the importance of epigenetic modifications such as post-translational modifications of histones, including methylation, acetylation, phosphorylation, ubiquitination, and their role in the activation or suppression of gene expression during osteoblast differentiation. Further, we have emphasized the future advancements in the field of epigenetics towards orthopaedical therapeutics.     

RNA甲基化修饰调控和规律

表观遗传学修饰包括DNA、RNA和蛋白质的化学修饰,基于非序列改变所致基因表达和功能水平变化。近年来,在DNA和蛋白质修饰基础上,可逆RNA甲基化修饰研究引领了第3次表观遗传学修饰研究的浪潮。RNA存在100余种化学修饰,甲基化是最主要的修饰形式。鉴定RNA甲基化修饰酶及研发其转录组水平高通量检测技术,是揭示RNA化学修饰调控基因表达和功能规律的基础。本文主要总结了近年来本课题组与合作团队及国内外同行在RNA甲基化表观转录组学研究中取得的主要前沿进展,包括发现了RNA去甲基酶、甲基转移酶和结合蛋白,揭示RNA甲基化修饰调控RNA加工代谢,及其调控正常生理和异常病理等重要生命进程。这些系列研究成果证明RNA甲基化修饰类似于DNA甲基化,具有可逆性,拓展了RNA甲基化表观转录组学研究新领域,完善了中心法则表观遗传学规律。     

Advances in epigenetic modifications and cervical cancer research

Cervical cancer (CC) is an important public health problem for women, and perspectives and information regarding its prevention and treatment are quickly evolving. Human papilloma virus (HPV) has been recognized as a major contributor to CC development; however, HPV infection is not the only cause of CC. Epigenetics refers to changes in gene expression levels caused by non-gene sequence changes. Growing evidence suggests that the disruption of gene expression patterns which were governed by epigenetic modifications can result in cancer, autoimmune diseases, and various other maladies. This article mainly reviews the current research status of epigenetic modifications in CC based on four aspects, respectively DNA methylation, histone modification, noncoding RNA regulation and chromatin regulation, and we also discuss their functions and molecular mechanisms in the occurrence and progression of CC. This review provides new ideas for early screening, risk assessment, molecular targeted therapy and prognostic prediction of CC.     

Silencing of transgene expression in mammalian cells by DNA methylation and histone modifications in gene therapy perspective

DNA methylation and histone modifications are vital in maintaining genomic stability and modulating cellular functions in mammalian cells. These two epigenetic modifications are the most common gene regulatory systems known to spatially control gene expression. Transgene silencing by these two mechanisms is a major challenge to achieving effective gene therapy for many genetic conditions. The implications of transgene silencing caused by epigenetic modifications have been extensively studied and reported in numerous gene delivery studies. This review highlights instances of transgene silencing by DNA methylation and histone modification with specific focus on the role of these two epigenetic effects on the repression of transgene expression in mammalian cells from integrative and non-integrative based gene delivery systems in the context of gene therapy. It also discusses the prospects of achieving an effective and sustained transgene expression for future gene therapy applications.