The molecular mechanisms responsible for the initiation and progression of breast cancer are far from being understood. During the past decade, the somatic mutation theory of cancer, which refers to the genetic disorder of fatal acquisition of multiple mutations in key genes, has been revolutionized and became clear that the deregulation of epigenetic machinery and miRNAs play a role as equally essential as genetics in cancerogenesis. In this regard, Yu et al. (2007) demonstrated that depletion of let-7 is associated with enhanced tumorigenicity of breast cancer (Yu et al. 2007). Moreover, it has been shown that the overexpression of miR-21 in breast cancer confers increased invasion capacities and promotes tumor metastasis to the lung (Zhu et al. 2008) . One of the first studies regarding epigenetic control of miRNA expression in breast cancer was conducted by Scott et al. (2006) in SkBr3 breast cancer cell line (Scott et al. 2006); In this study, they observed that upon treatment of SkBr3 cells with the HDAC inhibitor LAQ824, the expression levels of 5 miRNAs were up- and 22 miRNAs were down-regulated, indicative of epigenetic control of miRNAs in breast cancer development.

It is worthy to mention that miR-9, which is expressed from three genomic loci (miR-9-1, miR-9-2 and miR-9-3), is one of the most important miRNA involved in the pathogenesis of various malignancies including breast cancer (Bandres et al. 2009; Lehmann et al. 2008; Roman-Gomez et al. 2009) . In this regard, Hsu et al. (2009) showed that xenoestrogen exposure may induce aberrant epigenetic repression of miR-9-3 in breast epithelial cells (Hsu et al. 2009). It has also been documented that in breast cancer, the miR-9-1 locus is highly methylated not only in invasive ductal carcinoma, but also in ductal carcinoma in situ and the intraductal component of invasive ductal carcinoma (Lehmann et al. 2008) . Epigenetic silencing of miR-9 and miR-124a together with miR-148a, -152, and −663 was also reported by Lehmann et al. (2008) in breast cancer (Lehmann et al 2008); Interestingly, they found that treatment of breast cancer cell lines with 5-Aza-CdR, a DNA demethylating agent, reactivates miR-9-1, but not the other hypermethylated miRNAs. These findings suggest that epigenetic silencing of miR-9 loci constitutes an important event in breast carcinogenesis. In a study by Lujambio et al. (2008) on breast cancer cells, it has been shown that the hypermethylation of miR-148 led to its downregulation as a result of reinforced overexpression of DNMTs which resulted in tumor growth and metastasis (Lujambio et al 2008) . Interestingly, upon treatment of the breast cancer cells with a DNA demethylating agent, reduced tumor growth and inhibition of metastasis were also documented through the reactivation of miR-148. In an study, Xu et al. (2013) found that DNMT1 expression, which is aberrantly upregulated in breast cancer and its overexpression is responsible for the hypermethylation of miR-148a and miR-152 promoters, and is inversely correlated with the expression levels of miR-148a/152 in breast cancer tissues; suggesting a negative feedback regulatory loop between miR-148a/152 and DNMT1 in breast cancer (Xu et al. 2013).

Worldwide, prostate cancer is one of the three most common cancers among males (Siegel et al. 2012) , is the second most commonly diagnosed neoplasia and the sixth leading cause of cancer death in males (Jemal et al 2011) , despite all the recent improvements in diagnosis and treatment. Evolving data supports an important role for epigenetic processes in the development of prostate cancer in addition to the genetic mechanisms. Epigenetic events, including microRNAs (miRNAs) deregulation, have been recognized as critical players in prostate carcinogenesis (Shen and Abate-Shen 2010; Van der Poel 2007) . In a study by Rauhala et al. (2010) it has been shown that miR-193b is an epigenetically silenced putative tumor suppressor in prostate cancer (Rauhala et al. 2010). They found an increased expression of 38 miRNAs upon treatment of prostate cancer cell lines with 5-Aza-CdR and trichostatin A; among these, a CpG island upstream of the miR-193b locus was methylated. They demonstrated that expressing miR-193b using pre-miR-193b oligonucleotides caused a significant growth reduction resulting from a decrease of cells in the S-phase of the cell cycle (Rauhala et al. 2010) . MiR-145 is another example of epigenetically regulated microRNAs involved in various cancers including prostate. In seven cancer cell lines with miR-145 hypermethylation, 5-Aza-CdR treatment dramatically induced miR-145 expression. In a study by Suh et al. (2011) it has been reported that miR-145 is silenced in prostate cancer through DNA hypermethylation and p53 mutation (Suh et al. 2011). In prostate cancer, HDAC-1 is a direct target of miR-449a, and the downregulation of miR-449a causes an overexpression of HDAC-1; Thus, the aberrant expression of miR-449a may contribute to the abnormal epigenetic patterns which occurs in prostate cancer. Transfection of MiR-449a has been shown to induce cell-cycle arrest, apoptosis and a senescent-like phenotype in the prostate cancer cells (Yang et al 2009) . Also, it has been shown that the upregulation of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), by miR-101 results in an aberrant tumor suppressor gene silencing via trimethylating histone H3 lysine 27 in both bladder and prostate cancer (Friedman et al. 2009; Varambally et al. 2008) . To screen for epigenetically silenced miRNAs in prostate cancer, Formosa et al. (2013) treated prostate normal epithelial and carcinoma cells with 5-Aza-CdR and subsequently examined for the expression changes of 650 miRNAs (Formosa et al. 2013). The results of this study point to miR-132 as a methylation-silenced miRNA with an antimetastatic role in prostate cancer controlling cellular adhesion.

Epigenetically regulated miRNAs not only are involved in the acquisition of prostate cancers invasive capabilities, but also they may contribute to a significant resistance to chemotherapy-induced apoptosis. Bhatnagar et al. (2010) found that miR-205 and miR-31 are significantly downregulated in WPE1-NB26 cell line, which is a highly malignant prostate cancer cell, as well as in other cell lines representing advanced-stage prostate cancers (Bhatnagar et al. 2010). They cloned the promoter region of the miR-205 gene and found this region to be hypermethylated in cell lines derived from advanced prostate cancers. Treatment with the DNA methylation inhibitor 5-Aza-CdR induced the expression of miR-205, downregulated Bcl-w, and sensitized prostate cancer cells to the chemotherapy-induced apoptosis; which indicates the key rule of miR-205 and miR-31 in the resistance to apoptosis in advanced prostate cancer (Bhatnagar et al. 2010) .

In a study by Lujambio et al. (2007) , the hypermethylation of miR-124a was reported in 13 of 27 (48 %) lung cancer specimens (Lujambio et al. 2007). Remarkably, immunostaining analyses of lung cancer specimens (n = 27) showed that the hypermethylation of miR-124a was associated with strong CDK6 expression and Rb phosphorylation; indicating that the epigenetic silencing of miR-124a in cancer cells leads to the CDK6 up-regulation. Let-7a-3, an epigenetically regulated miRNA with an oncogenic function, belongs to the archetypal let-7 miRNA gene family and can be regulated by the DNMT1 and DNMT3B (Brueckner et al 2007) . The gene was normally silenced by a promoter hypermethylation in normal human tissues but was hypomethylated in some lung adenocarcinomas. Brueckner et al. (2007) reported that an elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes; which suggests epigenetic silencing of this oncogenic miRNA is a protective mechanism in lung cancer (Brueckner et al. 2007). Also, it has been demonstrated that miR-34a, which is a target of the tumor suppressor gene product p53, is silenced in seven of 24 (29.1 %) lung cancer specimens due to an aberrant CpG methylation of its promoter (Lodygin et al 2008) . This miRNA is recognized as tumor suppressor microRNA and its epigenetic silencing was reported to be a mechanism responsible for lung cancer pathogenesis.

In invasive lung cancer cells, hypermethylation in the promoter region of miR-200C was found to be responsible for the loss of its expression as evaluated by 5-Aza-CdR treatment of two highly aggressive lung cancer cell lines, H1299 and Calu-1 (Ceppi et al. 2010) . Furthermore, in the primary tumor specimens that were obtained from the non-small cell lung cancer (NSCLC) patients, a lower miR-200c expression level was found to be associated with a poor grade of differentiation and also with a higher propensity to lymph node metastases. Ceppi et al. (2010) found that the loss of miR-200c expression induces an aggressive phenotype in NSCLC; reintroduction of this miRNA into the highly invasive/aggressive NSCLC cells not only inhibits in vitro cell invasion, but also hinders in vivo metastasis formation as well (Ceppi et al. 2010). The MiR-29 family (miR-29a, b, and c) has been highlighted as a representative of epi-miRNA for targeting DNMT in various human cancers including lung cancer (Fabbri et al. 2007; Garzon et al. 2009; Nguyen et al. 2011) ; In this setting, an inverse correlation between the expression of miR-29s and DNMT-3A/-3B has been reported in lung cancer tissues. It has been shown that the elevated miR-29s can restore normal patterns of DNA methylation , leading to the release of overmethylated tumor suppressor genes, and inhibiting tumorigenicity in vitro and in vivo (Bartel 2009) .

In addition to the DNA methylatio n, contribution of histone modifications was also reported in the epigenetic silencing of miRNAs in lung cancer. In this regard, Incoronato et al. (2010) identified histone modifications rather than DNA hypermethylation as epigenetic events that regulated miR-212 levels, which is strongly down-regulated in lung cancer (Incoronato et al. 2010). Moreover, this study showed that miR-212 silencing via histone modifications is correlated to the severity of the disease since it is significantly down-regulated in T3/T4 staging rather than in T1/T2 staging. It is worth mentioning that the epigenetic control of miRNA might be tissue specific, as none of the miRNAs showed a statistically significant change in the increased expression after treatments of A549 and NCI-H157 lung cancer cell lines with either demethylatin agent 5-azacytidine (5-aza-C) and/or HDAC inhibitor TSA (Yanaihara et al. 2006) .

To identify epigenetically silenced miRNAs in colorectal cancer (CRC), Toyota et al. (2008) screened for miRNAs induction in CRC cells by 5-Aza-CdR treatment (Toyota et al. 2008). They found that miR-34b and miR-34c are epigenetically silenced in CRC and that the 5-Aza-CdR treatment rapidly restored the expression of these miRNAs. Methylation of the miR-34b/c CpG island was frequently observed in 100 % (nine of nine) and in 90 % (101 of 111) of CRC cell lines and primary CRC tumors, respectively. Interestingly, transfection of precursor miR-34b or miR-34c into CRC cells induced dramatic changes in the gene expression profile, and there was a significant overlap between the genes that were down-regulated by miR-34b/c and those that were down-regulated by 5-Aza-CdR (Toyota et al. 2008) . The relationship between miRNA and the cognate host gene epigenetic regulation was studied by Grady et al. (2008) . Simultaneous epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL (Ena/Vasp-like) was reported in 86 % of colorectal adenocarcinomas and in 67 % of adenomas, which indicates that aberrant methylation at this locus is an early common event in colorectal carcinogenesis. Grady et al. (2008) also showed that the combined treatment of 5-aza-C with an HDAC inhibitor restored simultaneous expression of EVL and miR-342. Furthermore, reconstitution of hsa-miR-342 in the colorectal cancer cell line HT-29 induced apoptosis, suggestive of a proapoptotic tumor suppressor function for this miRNA (Grady et al. 2008) .

In order to analyze the epigenetic regulation of miRNA genes in colorectal cancer, Suzuki et al. (2011) conducted a genome-wide profiling of the histone modifications (H3K4me3, H3K27me3, and H3K79me2) (Suzuki et al. 2011). By comparing miRNA expression and histone modification before and after DNA demethylation, 47 miRNAs, including miR-1-1 which acts as a tumor suppressor, was found to be potential targets of epigenetic silencing in early and advanced CRCs (Suzuki et al. 2011). To identify tumor-supressor miRNAs that were silenced through aberrant epigenetic events in CRC, Bandres et al. (2009) identified 5 miRNAs located around/on a CpG island that were down-regulated in patient with colorectal cancer (Bandres et al. 2009). Combined treatment of 3 CRC cell lines with a DNA methyltransferase inhibitor and a HDAC inhibitor restored the expression of 3 of the 5 microRNAs (miR-9, miR-129 and miR-137); this suggests that the aberrant DNA methylation and the histone modifications work together to induce silencing of miRNAs in CRC (Bandres et al. 2009). In a study done by Balaguer et al. (2010) , a contributing role was described for the epigenetic regulation of miR-137 in colorectal carcinogenesis (Balaguer et al. 2010). In this regard, methylation of the miR-137 CpG island was observed in virtually all CRC cell lines, 82 % of adenomas, and 82 % of CRCs, but only in 14 % of normal mucosae from the CRC patients and in 5 % of healthy subjects, which indicates a cancer-specific epigenetic event in CRC. Interestingly, using a systematic microarray and bioinformatics approaches, they identified LSD1, a histone demethylase, a target for miR-137 in the colon (Balaguer et al. 2010) .

Using MBD-isolated Genome Sequencing (MiGS) to evaluate genome-wide DNA methylation patterns combined with a microarray analysis to determine miRNA expression levels, Yan et al. (2011) searched for candidates miRNAs that were regulated by DNA methylation in HCT-116 colorectal cancer cell and found that 64 miRNAs were robustly methylated (Yan et al. 2011). They also showed that miR-941, miR-1237 and miR-1247 were up-regulated by 5-Aza-CdR treatment and transcribed independent from their respective putative host genes (Yan et al. 2011). To address if the same epigenetic disruption can “hit” miRNAs in transformed cells, Lujambio et al. (2007) have used HCT-116 colon cancer cells and double knockout DNMT1 and DNMT3b (DKO) cells to compare the miRNA expression profile of DKO and HCT-116 wild-type cells (Lujambio et al. 2007) . Among the dysregulated miRNAs, bisulfite genomic sequencing analyses of multiple clones of the original HCT-116 cells showed dense CpG island hypermethylation for miR-124a, miR-517c, and miR-373. Unlike miR-517c and miR-373 which were found to be densely methylated in normal colon tissues, the miR-124a–embedded CpG island was always unmethylated in normal counterparts. In the case of primary colorectal tumors, the miR-124a hypermethylation was observed in 75 % of patients. It is important to note that the presence of miR-124a hypermethylation was not a feature of this particular cell line, but analyzing a comprehensive collection of human cancer cell lines (n = 22) and primary samples (n = 171) from colon, breast, and lung carcinomas, leukemias, and lymphomas also showed a frequent presence of miR-124a hypermethylation (Lujambio et al. 2007).

To identify any miRNA genes that are harboring CpG island s undergo a methylation-mediated silencing in hepatocellular carcinoma (HCC), Furuta et al. (2010) examined the methylation status of 43 loci containing CpG island s around 39 mature miRNA genes in a panel of HCC cell lines and non-cancerous liver tissues as controls (Furuta et al. 2010). Among 11 miRNA genes that were frequently methylated in HCC cell lines but not in non-cancerous liver tissues, miR-124, miR-203 and miR-375 were selected as silenced miRNAs through the CpG-island methylation. They also demonstrated that only miR-124 and miR-203 are silenced by CpG island methylation in the primary tumors of HCC (Furuta et al. 2010). In a similar study, Datta et al. (2008) analyzed the miRNA expression profile in HCC cell lines treated with 5-aza-C and/or trichostatin A and found that these epigenetic drugs differentially regulate expression of a few miRs, particularly miR-1-1 (Datta et al. 2008). The results of this study showed that the miR-1 expression is markedly reduced by an aberrant CpG island methylation in HCC compared with matching liver tissues. They found that the miR-1-1 gene was hypomethylated in DNMT1 -null HCT-116 cells (but not in DNMT3B -null cells), this suggests an important role for the maintenance DNMT in the silencing of this particular miRNA. In addition, an ectopic expression of miR-1 in HCC cells caused an inhibition of cell growth and reduced replication potential (Datta et al 2008) . All together, these findings indicate that specific miRNAs including miR-1, miR-124 and miR-203 are tumor-suppressor miRNAs that inhibit their target oncogenes and are epigenetically silenced during hepatocarcinogenesis.

To identify miRNAs which are involved in the regulation of the abnormal DNA methylation in HBV-related HCC, miR-152 was found to be frequently down-regulated in the HBV-related HCC tissues in comparison with adjacent noncancerous hepatic tissues (Huang et al. 2010) . Huang et al. (2010) found that miR-152 was inversely correlated to the DNMT1 mRNA expression and may act as a tumor suppressor via suppression of this DNA methyltransferase. Interestingly, The forced expression of miR-152 in liver cell lines resulted in a marked reduction in the expression of DNMT1 at both mRNA and protein levels (Huang et al. 2010). In a recent study, Liu et al. (2013) reported that down-regulation of tumor suppressive miR-517a and miR-517c contribute to the HCC development; they found that ectopic expression of these miRNAs inhibits cell proliferation by blocking the G2/M transition, whereas down-regulation of miR-517a and miR-517c facilitates cell growth (Liu et al. 2013a) . In addition to the DNA methylation, the histone acetylation has been shown to play important roles in the pathogenesis of the HCC, and aberrations in this important epigenetic mechanism have been frequently observed in this malignancy. In a study conducted by Yuan et al. (2011) , they found that miR-200a and the level of histone H3 acetylation at its promoter were reduced in human HCC tissues as compared to adjacent noncancerous hepatic tissues (Yuan et al. 2011). They also found that a decreased expression of miR-200a and reduced histone acetylation level at the promoter region of this miRNA were induced through the activation of HDAC4 in a Sp1-dependent pathway. All together, the findings of this study suggest that the HDAC4/Sp1/miR-200a regulatory network induces the down-regulation of the miR-200a and the up-regulation of HDAC4 in HCC (Yuan et al. 2011).

miR-224 is one of the most commonly up-regulated microRNAs in HCC, it affects crucial cellular processes such as apoptosis and cell proliferation. In an effort to elucidate molecular mechanism that leads to the overexpression of miR-224 in HCC, Wang et al. (2012) found that the overexpression of E1A binding protein p300 (EP300) may account, in part, for the up-regulation of this miRNA in patients with HCC (Wang et al. 2012). Also, in an effort to investigate the epigenetic mechanisms responsible for the increased expression of miR-191 in HCC, hypomethylation of this miRNA locus was reported as the causative reason of the aberrancy; leading to an increased cell invasion and to the transition of the HCC cells into mesenchymal-like cells. In this regard, treatment of normal liver cells with 5-aza-C also induced an up-regulation of miR-191 expression, which suggests miR-191 involvement in the HCC progression (He et al. 2011) .

The role of aberrant epigenetic modifications, particularly DNA hypermethylation of gene promoters and miRNAs, is a frequent mechanism of gene silencing that contributes to the pathogenesis of acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) (Alvarez et al. 2010; Davidsson et al. 2009; Figueroa et al. 2010; Lugthart et al. 2011; Martin-Subero et al. 2009; Milani et al. 2010; Román-Gómez et al. 2007; Stumpel et al. 2009) . Overall, the methylation of miRNAs is found in a lower percentage of patients with AML in comparison with those with ALL. Using ALL cell lines, Roman-Gomez et al. (2009) demonstrated that 11 CpG islands that were embedded or closed to 13 miRNAs (miR-9-1, miR-9-2, miR-9-3, miR-10b, miR-34b, miR-34c, miR-124a1, miR-124a2, miR-124a3, miR-132, miR-196b, miR-203 and miR-212) disclosed in a closed chromatin conformation (decrease of 3mK4H3 and/or increase of 2mK9H3), which is associated with repressive gene expression (Roman-Gomez et al. 2009). Using bone marrow samples from 353 ALL patients at diagnosis, miRNAs methylation of at least one of the 13 miRNAs (methylated group) was also found in 65 % of the cases, supporting the role of the miRNA methylation in the early phases of lymphoid leukemogenesis. In addition, the downregulation of miRNAs expression reverted by a treatment with 5-Aza-CdR, suggesting that the expression of these miRNAs were regulated by epigenetic changes. They found that the patient-specific methylation profile provides important prognostic information in ALL and patients that belonged to the methylated group showed a significantly higher relapse and mortality rate (Roman-Gomez et al. 2009). Moreover, the methylation profile may be applied to redefine the prognosis in the selected ALL groups with well-established prognostic features; in this regard, the general poor outcome of BCR/ABL-positive or high-WBC-count ALL patients was improved in patients without miRNA hyper-methylation, whereas the general good outcome of the TEL/AML1-positive ALL patients was significantly worsened in those patients with the presence of miRNA methylation (Roman-Gomez et al. 2009). Findings in a study by Bueno et al. (2008) showed that genetic and epigenetic silencing of miR-203 enhanced ABL1 and BCR-ABL1 oncogene expression (Bueno et al. 2008) ; knowing that miR-203 is aberrantly methylated in ALL (Chim et al. 2011) , it is reasonable to hypothesize that silencing of this miRNA may provide a proliferative advantage in the BCR-ABL1-positive leukemia. It has been identified that from 11 miRNAs which were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation, seven of which (miR-10a, miR-152, mir-200a, miR-220b, miR-429, miR-432 and miR-503) were re-activated after exposure to the DNA methyltransferase inhibitor Zebularine (Stumpel et al. 2011) .