Mini-reviewDNA methylation in thoracic neoplasms
Introduction
Thoracic neoplasms, including lung cancer, esophageal carcinoma, and thymic epithelial tumors (TETs), are the leading cause of tumor-related death and a major health concern worldwide [1], [2], [3], [4], [5]. Prevention, diagnosis, treatment, and prognosis of these tumors are challenging, emphasizing the need for developing new diagnostic and therapeutic strategies. Surgical tumor removal is currently the most commonly employed treatment option. However, the value of surgery is limited by the fact that it depends strongly on early diagnosis, and current screening methods – based on testing for radiological and clinical features – are either too costly or not sensitive enough to routinely detect early stage thoracic neoplasms [6], [7], [8], [9], [10], [11]. The development of alternative screening tests would thus improve the clinical management of thoracic neoplasms and improve patient outcomes.
A number of molecular features have been associated with the development and progression of thoracic neoplasms. In addition to genetic changes, including gene mutations, loss of heterozygosity or homozygous deletions, and chromosomal rearrangements [2], [12], characteristic epigenetic alterations have been found to be associated with tumorigenesis. These findings have broadened our understanding of non-genetic mechanisms underlying thoracic neoplasms and their relationship with environmental susceptibility factors. Furthermore, specific changes in epigenetic profiles have been associated with early stages of tumor development, and thus have the potential to be used as markers for screening and diagnosis [13], [14]. Moreover, since epigenetic alterations are reversible, therapeutic restoration of epigenetic states may provide a new avenue for the development of novel anti-cancer treatments [15], [16], [17], [18]. In this review, we explore the role of epigenetic alterations in the onset and progression of thoracic neoplasms, as well as the potential utility of characteristic changes in DNA methylation patterns for the development for diagnostic tests and therapeutic interventions.
Epigenetic traits include DNA methylation and histone modifications. The control of these is important for proper cellular function, and is therefore critical for normal development and health [19]. Alterations to the levels of DNA and histone modifications, can affect the transcription of genes involved in the regulation of cell growth, differentiation, transformation, and apoptosis. Not surprisingly, aberrant epigenetic regulation has also been found to be an important driving force in the initiation and progression of cancer [20], [21]. In this review, we provide an overview of the relationship between epigenetic alterations, especially DNA methylation, and the development of thoracic neoplasms.
Methylation of deoxycytosine bases in CG pairs has a profound effect on gene expression. DNA methyltransferase (DNMT) enzymes establish and maintain methylation patterns by catalyzing the addition of a methyl group onto the fifth carbon of the pyrimidine ring of cytosine residues within CpG dinucleotides, forming 5-methylcytosine bases (5-MC; Fig. 1A). Alterations to CpG methylation patterns have been shown to contribute to cancer in two ways. First, hypermethylation of gene promoters or first exons can lead to transcriptional silencing. Notably, the expression of some tumor suppressor genes (TSGs) is affected in this manner in certain cancers (Fig. 1B; [22], [23], [24], [25]). Second, hypomethylation of intergenic and intronic sequences in proto-oncogene regions of the genome is believed to cause chromosomal instability [19], [26], [27], [28]. These alterations are often associated with changes in the expression of DNMT genes [29], [30]. Recent studies indicate that gene-specific hypermethylation, global DNA hypomethylation, and overexpression of DNMTs are early events in many human malignancies, including lung cancer, esophageal cancer and TETs [31], [32], [33]. Because these manifestations occur early in tumorigenesis and are characteristic of distinct cancer types, they could represent targets for early diagnosis, prevention, and treatment.
Section snippets
DNA hypermethylation and thoracic neoplasms
It is now recognized that not only genetic mechanisms, but also aberrant DNA methylation, can provide one or both of the hits postulated in Knudson’s two hit hypothesis for the inactivation of tumor-related genes [34]. DNA hypermethylation of promoter regions has been shown to be part of the mechanism by which TSGs are silenced in human cancers. Indeed, the average number of methylation-silenced genes in a single tumor is estimated to be approximately 400 [35]. Recent studies show that
Global DNA hypomethylation and thoracic neoplasms
In addition to loci-specific alterations of DNA methylation, global DNA hypomethylation is often a feature of tumorigenic cells [32], [88], [89], [90]. Although DNA hypomethylation in cancer tissue was first observed more than two decades ago [91], [92] and may be linked to carcinogenesis [93], the exact mechanism and biological significance of this association remains poorly understood [19]. A recent study demonstrated that the loss of DNA methylation in cancer may have two important
DNMTs and thoracic neoplasms
In mammalian genomes, there are three DNMT genes; DNMT3a and DMMT3b are responsible for de novo methylation and modify unmethylated DNA, whereas DNMT1 is thought to be responsible for maintaining methylation patterns by acting on hemi-methylated DNA [99]. A number of studies have reported that DNMT activity is increased in cancer cells, and may be related to tumor aggressiveness and poor patient prognosis [100], [101], [102], [103], [104]. In particular, Lin et al. investigated the upregulation
Conclusion
Tumorigenesis is a multistep process involving the accumulation of deleterious genetic as well as epigenetic changes. Aberrant DNA methylation has been repeatedly observed in thoracic neoplasms, particularly in lung cancer, esophageal carcinoma, and TETs. It is also now recognized that promoter hypermethylation of TSGs, global DNA hypomethylation, and over expression of DNMTs are all important events in the progression of tumorigenesis. These findings provide not only new insights into the
Conflicts of interest
There is no any financial/commercial conflicts of interests involving in this study.
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