**5. Polycom complex-mediated epigenetic silencing**

Polycomb group proteins (PcG) play an important role as regulators of stem cell pluripotency and differentiation [74], as well as inappropriate gene expression during cancer transformation [75, 76]. In mammals, two main Polycomb repressor complexes (PRCs) have been discovered. PRC-2 is an initiating complex that causes trimethylation of histone 3 lysine and contains the subunits EZH1/EZH2, SUZ12, EED, and RBAP46/48 (H3K27Me3).

PCAF, PHC, RING1, CBX, and BMI1 are components of the housekeeping complex PRC-1, which mediates the ubiquitination of H2AK119 (H2AK119Ub). CRC recruitment and heterochromatin growth are aided by these histone marks, which are frequently detected in the context of DNA hypermethylation and gene suppression [75, 76]. Several proteins, such as including JARID2 and members of the sex comb-like family (ASXL), interact with EZH2 and SUZ12 to lead PRC-2 to polykyl response elements (PRE) throughout the genome [77, 78]. Goto et al. [79] investigated gene repression in MPM and observed that a subset of genes repressed in MPM had H3K27Me3 without DNA hypermethylation, implying that disruptions in polycomb gene expression may play a role in MPM etiology [80, 81].

Several immunoblotting investigations studies revealed that MPM cells overexpress EZH2 with associated increases in H3K27Me3 levels when compared to normal mesothelial cells. Another set of tests, which included QRT-PCR, immunoblotting, and IHC, revealed that EZH2 was overexpressed in almost 80% of primary MPMs (most of which were epithelioid histology). As a result of these findings, it was

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

identified that EZH2 is overexpressed in MPM and that PRC-2 could be considered as a potential therapeutic target in these cancers. The overexpression of EZH2 in MPM was verified by TCGA analysis, as was a strong link between EZH2 upregulation and lower MPM patient survival (**Figure 2A**). Further TCGA analysis reveals that SUZ12 overexpression is associated with poor survival in MPM patients (**Figure 2B**). On the other hand, there is no evidence about MPM patients' survival related to EED expression (**Figure 2C**).

The foregoing findings are especially important in light of recent findings that inactivating mutations in BRCA-associated protein 1 (BAP1), which encodes a nuclear ubiquitin hydrolase with several functions, are found in uncommon familial MPMs as well as almost 60% of sporadic MPMs. H2AK119Ub is ubiquitinated, for example.

LaFave et al. [82] discovered that BAP1 mutations, which are linked to protein expression loss, enhanced the expression of EZH2 and SUZ12 in MPM cells in a series of experiments. Likewise, overexpression of EZH2 was related to lower levels of H4K2Me1 and less occupancy of L3MBTL2 (an unusual polycomb protein that identifies this repressive histone mark) inside the EZH2 promoter in BAP1 mutant cells. Despite the strong connection between BAP1 mutations and repression of Polycomb stem cell targets, no specific clinical manifestation of BAP1 mutant MPM has been identified. Somatic mutations in BAP1 appear to be more common in current or past smokers with MPM [83].
