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Review
. 2023 May 9;15(10):2683.
doi: 10.3390/cancers15102683.

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

Kazem Nejati-Koshki  1 , Chris-Tiann Roberts  2 , Ghader Babaei  3 , Mojgan Rastegar  2
Affiliations
Review

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology

Kazem Nejati-Koshki et al. Cancers (Basel). .

Abstract

Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.

Keywords: DNA methylation; MeCP2/MeCP2 isoforms; cancer biology; epigenetics; oncogene; tumor suppressor gene.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of suspected roles of and molecular pathways involving MeCP2 in breast cancer. DNA hypermethylation, histone hypoacetylation, H3K9 methylation, and binding of MeCP2, and other proteins shown in this Figure that will contribute to ER silencing [103]. Binding of MeCP2 to the hypermethylated of CpG sites in the proximal region of the KLK6 promoter silences the KLK6 gene [105]. Binding of MeCP2 to the promoter region of RPLL1 and RPL5 reduces the expression levels of their respective proteins and disrupts their inhibitory activity in ubiquitination-mediated p53 degradation alongside the binding to MDM2 [35]. MeCP2 acetylation levels are regulated by the interaction between SIRT1, ATRX, and HDAC1 in breast cancer [106]. Recruitment of MeCP2 to the methylated regions of CLDN6, along with deacetylation of histones H3 and H4, results in the invasion and migration capacity of breast-cancer cells [107]. MeCP2 inhibition by miR-194-3p may be achieved via binding to the MECP2 3′-UTR. However, linc-ROR acts as a competitive endogenous RNA for miR-194-3p [108]. MeCP2, in relation to MeCP2-mediated regulation of tumor-suppressor genes, is found in association with the PIP5K, RASSF1A, ENPP4, and RARB2 gene promoters [109]. Illustration is generated using BioRender.com.
Figure 4
Figure 4
Schematic representing the suggested roles of and molecular pathways that link MeCP2 to gastric-cancer progression. MeCP2-mediated activation of Wnt5a/β-Catenin signaling via FOXF1 inhibition promotes cell proliferation, while MeCP2-mediated inhibition of the caspase-3 signaling via MYOD1inhibition promotes apoptosis [93]. Inhibition of MeCP2 may be achieved by miR-638. Binding of MeCP2 to the promoter region of GIT1 increases GIT1 expression. GIT1 activates the MEK1/2-ERK1/2 signaling pathway and promoted cell proliferation [120]. Expression levels of MeCP2 are reduced by the binding of miR-212 to the MECP2 3′UTR region [121]. Upregulation of MeCP2 results in increased expression of NOX4 via binding of MeCP2 to the NOX4 promoter region and upregulation of the NOX4/PKM2 pathway in 5-FU resistance [123]. Inhibition of MTHFD2 and MTHFR, and increased level of PTEN, p16, p21, and RASSF1A, by the action of miR-22, results in decreased cell proliferation. However, MeCP2-mediated inhibition of miR-22 deregulates tumor suppression through the action of miR-22 in gastric-cancer cells [124]. Gastric-cancer cell proliferation is due to MeCP2-mediated inhibition of miR-338-3p and miR-338-5p [125]. Illustration is generated using BioRender.com.
Figure 5
Figure 5
Schematic representing the suspected roles of and molecular pathways involving MeCP2 in hepatocellular carcinoma (HCC). Hypermethylation of the TTP promoter, and subsequent repression of TTP expression, is involved in the downregulation of TGF-β1 signaling in the progression of HCC via the recruitment of HDAC complexes by MeCP2 [126]. Activation of the ERK1/2 signaling pathway and inhibition of p38 activity by MeCP2 promotes cell proliferation in HCC [127]. Binding of MeCP2 and CREB1 to the hypermethylated HOXD3 promoter increases the expression of HOXD3. Binding of HOXD3 to the HB-EGF promoter results in increased HB-EGF activation and increased cell invasion and migration of HCC cells [129]. Negative regulation of MeCP2 in sorafenib resistance by miR-1324 is alleviated in the presence of circFOXM1, leading to increased expression levels of MeCP2 [130]. Illustration is generated using BioRender.com.
Figure 2
Figure 2
Schematic representing the suspected roles of and molecular pathways involving MeCP2 in colorectal-cancer progression. MeCP2 leads SPI1 to the ZEB1 promoter to increase ZEB1 expression. Increased ZEB1 expression leads to upregulation of MMP14, SOX2, and CD133 [91]. MeCP2-mediated regulation of KLF4 is achieved through the binding of MeCP2 to METTL14. Complexing of MeCP2 and METTL14 results in decreased m6A methylation, and destabilization of KLF4 transcripts and CRC metastasis [111]. MeCP2, in conjunction with DNA methylation at the promoter region, regulated the expression of E-cadherin in CRC [112]. MeCP2-mediated epigenetic silencing of miR-137 is also shown [113]. Illustration is generated using BioRender.com.
Figure 3
Figure 3
Schematic representing the suggested roles of and molecular pathways involving MeCP2 in pancreatic cancer. MeCP2 increases mesenchymal markers including snail, N-cadherin, and vimentin. MeCP2 simultaneously decreases epithelial markers including E-cadherin and ZO-1 to induce EMT. The increase and decrease of mesenchymal and epithelial markers, respectively, are achieved through the binding of MeCP2 to the Furin promoter and subsequent activation of TGF-β1 by Furin and Smad phosphorylation [115]. MeCP2 recruitment to the methylated CpG islands of LIN28A hinders the ability of LIN28A to increase the expression of NANOG, c-Myc, OCT4, SOX2, and LIN28B [116]. MeCP2 binding to methylated CpG sites at the IL-6 gene may result in its silencing [117]. Illustration is generated using BioRender.com.
Figure 6
Figure 6
Schematic representing the suspected roles of and molecular pathways involving MeCP2 in prostate-cancer progression. The suppression of the KAI1 metastasis suppressor gene due to alterations in methylation patterns at the KAI1 CpG-methylation sites within the promoter region allows for the binding of MeCP2 and subsequent reduction of KAI1 in prostate cancer cells [132]. Hypermethylation of the TIMP-2 promoter facilitates the binding of MeCP2 to affect TIMP-2 expression at the invasive and metastatic stages of prostate-cancer progression [133]. Transcriptional repression of GADD45α by the binding of MeCP2 to four aberrantly methylated CpG sites upstream of the proximal promoter region results in the silencing of GADD45α. Downregulation of MeCP2 or administration of DNMT inhibitors to increase expression of GADD45α may result in increased sensitivity to docetaxel chemotherapy [134]. Inhibition of TRIM24 may be achieved by the binding of miR-137 to the TRIM24 3′-UTR promoter region. However, inhibition of miR-137 by MeCP2 reduces miR-137 expression via increased miR-137 promoter methylation [135]. Illustration is generated using BioRender.com.
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