Aberrant Epigenetic Silencing of Tumor Suppressor Genes Is Reversed by Direct Reprogramming

Stem Cells ◽  
2010 ◽  
Vol 28 (8) ◽  
pp. 1349-1354 ◽  
Author(s):  
Shulamit Ron-Bigger ◽  
Ori Bar-Nur ◽  
Sara Isaac ◽  
Michael Bocker ◽  
Frank Lyko ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Epigenetic Silencing ◽  
Direct Reprogramming ◽  
Suppressor Genes

Establishment of Myelodysplastic Syndrome-Specific Methylome: Implications for the Pathogenesis of Clonal Evolution and Association with Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 850-850
Author(s):  
Rrebecca D ganetzky ◽  
Ying Jiang ◽  
Courtney Prince ◽  
Mikkael A. Sekeres ◽  
Yogen Saunthararajah ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Methylation Level ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Epigenetic Silencing ◽  
Methylation Analysis ◽  
Suppressor Genes ◽  
Cpg Sites ◽  
Disease Specific

Abstract Epigenetic silencing of genes, such as tumor suppressor genes (TSG), throughaberrant promoter hypermethylation has been implicated in the pathogenesis of MDS. Epigenetic silencing may cooperate with chromosomal abnormalities to completelysilence a TSG or duplication of methylated alleles through UPD could potentially leadto complete TSG silencing. Hypomethylating agents can reverse aberrant silencing;however targeted application of epigenetic therapy is not possible, as ypermethylatedsites relevant to MDS pathogenesis remain mostly unknown. Traditional echnologieslimited methylation analysis to a small number of individual loci; as a result, there has been a lack of systematic studies on the methylation pattern in MDS. New methylationarray techniques allow for rapid polygenic analysis of methylation and the stablishmentof tissue- and disease-specific methylomes. We hypothesized that using ethylationarrays (Illumina®) aberrantly hypermethylated CpG sites and whole methylation patternspathognomic for MDS can be identified. First, we compared patients with MDS andAML (n=240) to controls (n=64) using low-density methylation arrays (1,505 CpG sites)to explore the general applicability of whole genome methylation arrays. We hen usedhigh density arrays (27,578 CpG sites) to fully explore a disease-specific ethylome in a representative sub-cohort of MDS/AML patients. We developed ananalytic algorithm that included establishment of the methylome of normal marrow as a reference and analysis of concordantly hypermethylated genes in patients, using methylation status as either a continuous or dichotomized variable. Global methylation analysis demonstrated that there was concordant hypermethylation in 25% and 50% of MDS patients in 1,199 CpG and 93 CpG sites, respectively, and in 25% and 50% of high-risk MDS patients at 1,816 and 288 CpG sites, respectively. The average methylation level was significantly higher in MDS than in controls and was associated with IPSS score (p=.06). The methylation pattern in MDS include aberrant hypermethylation of tumor suppressor genes (DCC, HIC1), and genes involved in DNA repair (OGG1, MGMT), cell cycle control (DBC1), development and differentiation (HOXA5, HOXB6) and apoptosis (ALOX12). Analysis of the most frequently aberrantly methylated genes identified several genes and we used FZD9 as a candidate TSG on chromosome 7 as an illustrative example for further analysis. Methylation level at this site was significantly predictive of survival in proportional hazards regression analysis (p=.002) and inversely correlated with expression of FZD9 mRNA. Using high density arrays to examine methylation status at locations most commonly associated with chromosomal lesions in MDS (chromosome 5, 7, 11, 13 and 20), we discovered 8 genes with functions and tissue expression patterns suggestive of involvement with MDS. Of these genes, 7 have previously been reported to be aberrantly hypermethylated in malignancy. Patients who did not exhibit hypermethylation at any of these sites were less likely to have developed AML (OR = 4.2, p = 0.074) and showed prolonged survival (p =.09). The absence of hypermethylation at one of the 8 pathognomonic sites was significantly predictive of survival (p=.05). In conclusion, genetic silencing by hypermethylation can produce molecular phenotypes identical to loss of function mutations and deletion of genetic information; however, unlike genetic lesions, epigenetic lesions are more common and are reversible by hypomethylating therapy. Development of a predictive algorithm based on methylation data will allow targeted therapy with epigenetic therapies.

Abstract 196: UHRF1 is upregulated in prostate cancer and induces epigenetic silencing of tumor suppressor genes

2010 ◽  
Author(s):  
Paolo Kunderfranco ◽  
Laura Curti ◽  
Federica Babbio ◽  
Christian Pistore ◽  
Marco Magistri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Epigenetic Silencing ◽  
Suppressor Genes

scholarly journals Id1 overexpression is independent of repression and epigenetic silencing of tumor suppressor genes in melanoma

Epigenetics ◽  
2010 ◽  
Vol 5 (5) ◽  
pp. 410-421 ◽  
Author(s):  
Megan A. Healey ◽  
Staci L. Deaton ◽  
Jonathan K. Alder ◽  
Véronique Winnepenninckx ◽  
Robert A. Casero Jr. ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Epigenetic Silencing ◽  
Suppressor Genes

scholarly journals The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 127
Author(s):  
Adelaide Ohui Fierti ◽  
Michael Bright Yakass ◽  
Ernest Adjei Okertchiri ◽  
Samuel Mawuli Adadey ◽  
Osbourne Quaye
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Epstein Barr Virus ◽  
Epigenetic Silencing ◽  
Gene Products ◽  
Suppressor Genes ◽  
Barr Virus ◽  
Tumor Suppressor Proteins ◽  
Epstein Barr

Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.

scholarly journals Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential

2016 ◽  
Vol 1865 (2) ◽  
pp. 275-288 ◽  
Author(s):  
Anna Kazanets ◽  
Tatiana Shorstova ◽  
Khalid Hilmi ◽  
Maud Marques ◽  
Michael Witcher
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Epigenetic Silencing ◽  
Suppressor Genes

Insulation of tumor suppressor genes by the nuclear factor CTCF

2011 ◽  
Vol 89 (5) ◽  
pp. 479-488 ◽  
Author(s):  
Félix Recillas-Targa ◽  
Inti A. de la Rosa-Velázquez ◽  
Ernesto Soto-Reyes
Keyword(s):  
Tumor Suppressor ◽  
Rna Polymerase Ii ◽  
Tumor Suppressor Genes ◽  
Zinc Finger Protein ◽  
Epigenetic Silencing ◽  
Cancer Development ◽  
Promoter Regions ◽  
Suppressor Genes ◽  
Chromatin Remodelers ◽  
Relevant Role

One of the most outstanding nuclear factors, which has chromatin insulator and transcriptional properties and also contribute to genomic organization, is the zinc-finger protein CCCTC-binding factor (CTCF). Among its multiple functions, a growing amount of evidence implicates CTCF in the epigenetic regulation of genes responsible for the control of the cell cycle, and its mis-regulation can lead to aberrant epigenetic silencing of genes involved in cancer development. Detailed studies are now revealing that CTCF can serve as a barrier against the spread of DNA methylation and histone repressive marks over promoter regions of tumor suppressor genes. Moreover, new evidences points out to the capacity of CTCF to be covalently modified, in particular, through poly(ADP-ribosyl)ation with regulatory consequences. An unexplored aspect of CTCF is its intergenic and intragenic distribution in certain loci. Such distribution seems to facilitate the formation of an optimal chromatin structure and the recruitment of chromatin remodelers with the possible incorporation of RNA polymerase II. Therefore, in the context of tumor suppressor genes and cancer development, CTCF appears to play a relevant role by incorporating a combination of mechanisms involved in the protection against epigenetic silencing components and the maintenance of optimal higher-order organization of the corresponding loci.

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