**3. Methylation-mediated suppressor gene silencing**

There are several studies that have shown a relationship between silencing suppressor gene by methylation process and the development of MPL. For example, Christensen et al. [23] examined the DNA methylation status of the promoter of six genes that regulate cell cycle progression at 70 MPM. The extent of methylation of these genes was correlated with lung asbestos burden and overall survival. Goto et al. [60] studied methylation process in more than 6000 GpC islands, comparing twenty MPM versus twenty lung adenocarcinomas, using microarray PCR technique. Their results are interesting because they found out that 387 genes (6.3%) were hypermethylated in mesotheliomas, while the number of hypermethylated gene in lung adenocarcinoma were higher with a total amount of 544 genes (8.8%).

MPL patients' survival is related with DNA methylation levels. In this way, higher levels of DNA methylation correlate with lower patient survival. Three genes; TMEM30B, KAZALD1 and MAPK13, are specifically hypermethylated in MPM. Several reports have documented tumor suppressor gene silencing related to DNA methylation process in MPM (**Table 1**) and there is evidence of hypermethylation of some of these genes affecting overall survival.

Currently, scientific evidence has shown that recurrent hypermethylation is highly related to tumor suppressor genes in MPM, however, the mechanisms behind this process have been poorly studied. Novel studies have identified TC2N gene as a tumorigenesis promoter by silencing p53. Cytokine signaling participate in modulation process of DNMT expression and mediate hypermethylation of target genes enrolled in some types of cancer such as colorectal carcinoma and erythroleukemia cells [61, 62]. Exposure to asbestos fibers leads to a cytokine cascade induced by high mobility group 1 (HMGB1) or the NLRP3 inflammasome. These cytokines use to change the regulation of the expression of DNMT and other components of the methylation machinery during the process of MPM evolution.

A study of a panel of genes encoding epigenetic regulators in a panel of cultured cell lines derived from asbestos-associated MPM relative to LP-9 (a commercially available normal mesothelial cell line) was recently carried out. Consistent with the study results, TCGA data demonstrate a spectrum of DNMT expression in MPM and suggest that overexpression of DNMT1, DNMT3A, and DNMT3B correlates with decreased survival of pleural mesothelioma patients (**Figure 2**).


#### **Table 1.**

*Hypermethylated genes related to MPM.*

*Epigenomics in Malignant Pleural Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.105408*

#### **Figure 2.**

*Association between intratumoral DNMT expression levels and surveillance in patients with MPM. The Kaplan Meier waves show that DNMT1, DNMT3A, and DNMT3B expression, measured by RNA-seq technique, has negative impact in patients' surveillance.*

Kim et al. [1] studied gene expression and methylation profiles in pluripotent populations (SP) and non-SP fractions in human MPM samples, using RNA-seq and methylated DNA immunoprecipitation techniques. They found 6400 hypermethylated genes and 3400 hypomethylated genes in SP. Seven hundred and ninety-five genes were upregulated, while three hundred and thirty-five were significantly repressed in SP compared to non-SP fractions. They looked at changes in DNA methylation and expression levels of 122 genes; 118 genes were hypermethylated and downregulated, while 4 were hypomethylated and upregulated. Ten other genes showed hypermethylation and low expression of CpG promoter islands.
