<i>MECP2</i> Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Neupane, Manish; Clark, Allison; Landini, Serena; Birkbak, Nicolai J.; Eklund, Aron C.; Lim, Elgene; Culhane, Aedín C.; Barry, William T.; Schumacher, Steven E.; Beroukhim, Rameen; Szállási, Zoltán; Vidal, Marc; Hill, David E.; Silver, Daniel P.

doi:10.1158/2159-8290.cd-15-0341

Cited by 54 publications

(41 citation statements)

References 70 publications

(72 reference statements)

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“…The lethality and recurrence of BC are blamed of metastasis to distant organs, and although the exact undergoing processes of metastasis are not fully understood because of complexity, the impact of epithelial-mesenchymal transition (EMT) clearly outshines and is undeniable [48]. Overexpression of methyl-CpG-binding protein (MeCP2) widely known as an oncogenic epigenetic modulator relevant to BC and acts in line with RAS, MAPK, and PI3K pathways to the extent that its down-regulation would be compensated by RAS overexpression in TN subtype [49]. Another metastasis inducer called A disintegrin and metalloprotease domain-containing protein 12 (ADAM-12) would be silenced by the regulatory axis of Z-DNA/MeCP2/NF1.…”

Section: Discussionmentioning

confidence: 99%

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Afzali

Salimi

2019

Preprint

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Circular RNAs (circRNAs) along other complementary regulatory elements in ceRNAs networks possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems biology tools and approaches to identify influential BC circRNAs, RNA binding proteins (RBPs), miRNAs, and related mRNAs to study and decipher the BC triggering biological processes and pathways.Rooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as super sponge having multiple miRNA response elements (MREs) for numerous miRNAs. Then four leading miRNAs (hsa-miR-149, hsa-miR-182, hsa-miR-383, and hsa-miR-873) accountable for BC progression were also introduced from merging several ceRNAs networks. The predicted 7-and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs-miRNAs network then were presented to STRING database to form the PPI network and deciphering the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs networks' members as targetable therapeutic elements. This study suggested extensive panels of novel covering therapeutic targets that are in charge of BC progression in every aspect, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs. Breast cancer (BC) is the most lethal cancer among women worldwide in 2017 [1]. To surpass the anti-cancer treatments' deficiencies, exploitation of all the novel high throughput data rooting from underlying microlayers of a disease is critical. Competing endogenous RNAs (ceRNAs) network which consists of various transcripts regulating each other at post-transcriptional level [2], is a complex and yet novel tracing means to investigate the breast cancer progression and metastasis. The interrelation between the transcripts that possess miRNA response elements (MREs), namely circular RNAs (circRNAs) and mRNAs is pivotal in the deciphering steps. The fundamental core of the ceRNA network is based on the ratio of affinity and competing for shared miRNAs MREs [3]. The circRNAs that were surmised to be non-coding, are now believed to be translated into proteins [4]. Apropos of being resistant to exonucleases and being more stable due to the lack of cap and poly A tales in their structure [5], possess myriad noteworthy functions in genes' expression regulations in cancer. They are divided into three subcategories regarding their source of emergence; exonic circRNA (ecRNA), exon-intron circRNA (ElciRNA)...

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Section: Discussionmentioning

confidence: 99%

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Afzali

Salimi

2019

Preprint

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“…Indeed, MeCP2, by virtue of its specific binding to methylated DNA, plays a very important role in cancer, 9,10 where the dysregulation of this epigenetic mark is a hallmark 11 that leads to important structural chromatin changes. 12 Moreover, MECP2 was recently shown to be a bona fide oncogene, 13 which is frequently amplified in several cancer types.…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity

et al. 2017

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MeCP2 binds to methylated DNA in a chromatin context and has an important role in cancer and brain development and function. Histone deacetylase (HDAC) inhibitors are currently being used to palliate many cancer and neurological disorders. Yet, the molecular mechanisms involved are not well known for the most part and, in particular, the relationship between histone acetylation and MeCP2 is not well understood. In this paper, we study the effect of the HDAC inhibitor trichostatin A (TSA) on MeCP2, a protein whose dysregulation plays an important role in these diseases. We find that treatment of cells with TSA decreases the phosphorylation state of this protein and appears to result in a higher MeCP2 chromatin binding affinity. Yet, the binding dynamics with which the protein binds to DNA appear not to be significantly affected despite the chromatin reorganization resulting from the high levels of acetylation. HDAC inhibition also results in an overall decrease in MeCP2 levels of different cell lines. Moreover, we show that miR132 increases upon TSA treatment, and is one of the players involved in the observed downregulation of MeCP2.

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“…Oncogenesis and tumor progression are the multistep and multifactorial process involving different genes, which is accompanied by alterations in a variety of gene expression patterns that in turn affect cancer cell survival, growth, cycle, apoptosis, migration and invasion regulated by these genes [27]. In recent years, accumulating evidence has certi ed that MECP2, as a key epigenetic regulator, plays an important oncogene role in several cancer types [18,28]. For examle, MECP2 expression is upregulated and promotes tumor progression in breast cancer, lung cancer, cervical cancer and uterine cancer [18].…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, accumulating evidence has certi ed that MECP2, as a key epigenetic regulator, plays an important oncogene role in several cancer types [18,28]. For examle, MECP2 expression is upregulated and promotes tumor progression in breast cancer, lung cancer, cervical cancer and uterine cancer [18]. It enhances oral squamous cell carcinoma and colorectal cancer growth, and facilitates oncogenesis and development of osteosarcoma and neuroblastoma [29,30].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that MECP2 not only suppresses gene transcription, such as inhibiting BDNF and Cdkl5 expressions, via binding to the methylated CpG islands and recruiting co-repressors (e.g., histone deacetylases and Sin3A), but also promotes gene transcription, such as facilitating GIT1 expression, through binding to the methylated CpG dinucleotides and recruiting activators (e.g., CREB1) [13][14][15][16][17]. In recent years, emerging evidence indicates the role of MECP2 as a crucial oncogene in several cancer types [18]. Our previous studies have found that MECP2 is upregulated in liver cancer and facilitates cell growth [19], it enhances breast cancer proliferation via facilitating ubiquitination-mediated P53 degradation by regulating RPL5/RPL11 expressions [20], and it promotes GC cell proliferation and suppresses cell apoptosis via restraining FOXF1/MYOD1 transcription and enhancing GIT1 transcription by binding to the methylated CpG sites of the promoter regions of FOXF1/MYOD1 [21,22].…”

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MECP2 promotes migration and invasion of gastric cancer cells via modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription

Zhao¹,

Wang²,

Yang³

et al. 2020

Preprint

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Background: Methyl-CpG-binding protein 2 (MECP2), an epigenetic regulatory factor, promotes the carcinogenesis and progression of a number of cancers. However, its role in the migration and invasion of gastric cancer (GC) as well as the underlying molecular mechanisms remain unclear.Methods: Immunohistochemistry (IHC), Western blot, and quantitative real-time PCR (qRT-PCR) were performed to measure the expressions of MECP2, FBXW7, c-Myc, mTOR and Notch1 in GC tissues and cell lines, respectively. The effects of MECP2 silencing and overexpression on GC cell migration and invasion were detected by wound healing assay and transwell assay. The mechanisms of MECP2-mediated migration and invasion were further investigated using chromatin immunoprecipitation sequencing (ChIP-Seq) and luciferase reporter gene assay.Results: In this study, we found that MECP2 facilitated the migration and invasion of GC cells. Investigation of the molecular mechanism revealed that MECP2 restrained FBXW7 transcription in GC by binding to the methylated CpG sites of FBXW7’s promoter region. MECP2 expression was remarkably negatively correlated with the FBXW7 level in GC tissues. FBXW7 expression was significantly downregulated in GC tissues and cell lines, and low FBXW7 expression was correlated with the clinicopathologic features. FBXW7 repressed cell migration and invasion by regulating the Notch1/c-Myc/mTOR signaling pathways, and knockdown of FBXW7 reversed the effects of silencing MECP2. Moreover, MECP2 upregulated the Notch1/c-Myc/mTOR signaling pathways by inhibiting FBXW7 expression at the transcription level.Conclusion: This study demonstrates that MECP2 promotes migration and invasion of GC cells via modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription. The findings suggest that MECP2 may be a novel effective therapeutic target for GC patients.

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MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy

Cited by 54 publications

References 70 publications

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity

MECP2 promotes migration and invasion of gastric cancer cells via modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription

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