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

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.

Methylated Nucleotide-Based Proteolysis-Targeting Chimera Enables Targeted Degradation of Methyl-CpG-Binding Protein 2

“…These advantages encompass multifaceted target engagement, augmented specificity, mitigation of off-target effects, pliability in modular design, and the potential for posttranslational modifications of target proteins, transcending the confines of mere downregulation. Lastly, despite substantial efforts dedicated to unraveling MeCP2-related signaling pathways, the downstream mechanisms induced by MeCP2 exhibit remarkable diversity. ,, The apoptosis pathway related to Bcl-2 and Bcl-xL has been investigated in the current work, but more detailed mechanisms demand further scrutiny and investigation. Nevertheless, methyl-PROTAC represents a novel concept in which modified nucleotides are successfully integrated into the PROTAC system, paving the way for nucleotide-based PROTACs to become a versatile platform in the future.…”

“…Lastly, despite substantial efforts dedicated to unraveling MeCP2-related signaling pathways, the downstream mechanisms induced by MeCP2 exhibit remarkable diversity. 20,50,51 The apoptosis pathway related to Bcl-2 and Bcl-xL has been investigated in the current work, but more detailed mechanisms demand further scrutiny and investigation. Nevertheless, methyl-PROTAC represents a novel concept in which modified nucleotides are successfully integrated into the PROTAC system, paving the way for nucleotide-based PROTACs to become a versatile platform in the future.…”

“…Epigenetic modification refers to the heritable alteration of deoxyribonucleic acid (DNA) without influencing the DNA sequence, , including DNA modifications and histone post-translational modifications. – DNA methylation refers to the covalent modification of the C-5 position of the cytosine ring (5-methylcytosine, 5 mC), which is catalyzed by DNA methyltransferases (DNMTs), , and this modification could be removed by a chain of reactions catalyzed by ten-eleven translocation (TET), thymine DNA glycosylase (TDG), and base excision repair enzyme (BER). , On the other hand, the methylated DNA could be specifically recognized by a pivotal reader protein, methyl-CpG-binding protein 2 (MeCP2), which has been implicated in the pathogenesis of neurological and neurodevelopmental disorders. – Intriguingly, MeCP2 has also been established as an oncogene and is upregulated in various types of human cancers. – However, due to the lack of the MeCP2 inhibitor, it remains a challenge to target MeCP2 for cancer treatment. – We and others have demonstrated that nucleotide-based proteolysis-targeting chimera (PROTAC) platforms are effective in degrading undruggable targets such as ribonucleic acid (RNA)-binding proteins, transcription factors, – G-quadruplex binding proteins, cellular Myc (c-Myc), and telomeric repeat-binding factor proteins (TRFs) . Thus, we aim to test whether the nucleotide-based PROTAC design can be adopted for targeted degradation of epigenetic readers such as MeCP2 in cancer cells.…”

The Killer’s Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer

“…DNA methyl binding proteins (MBDs) serve as epigenetic readers because they bind to methylated DNA and recruit enzymes that modify histones to coordinate chromatin processes. Mutations in MBD proteins have been identified in various human cancers and have been shown to be critical in the development of neoplasms [ 275 , 276 , 277 , 278 ].…”

Quinoline‐based thiazolyl‐hydrazones target cancer cells through autophagy inhibition

“…(methyl CpG binding protein 2), FBP1 (fructose-1,6-bisphosphatase 1), KMO (kynurenine 3-monooxygenase), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), myeloid leukemia 1 (MCL-1), human dihydroorotate dehydrogenase (hDHODH), eukaryotic translation initiation factor 4E (eIF4E), focal adhesion kinase 2 (FAK), tyrosinase (monophenol monooxygenase) were recognized as cancer-relevant targets. [56][57][58][59][60][61][62][63][64][65] Since KCNQ1, MeCP2, and FBP1 are included in cancer progression via various signaling pathways, [56][57][58] they are not selected for further docking studies. Also, tyrosinase is not studied in that respect since it is related to a specific cancer type, which is not studied in this project.…”