scholarly journals Genome-Wide Methylation Analysis and Epigenetic Unmasking Identify Tumor Suppressor Genes in Hepatocellular Carcinoma

2013 ◽  
Vol 145 (6) ◽  
pp. 1424-1435.e25 ◽  
Author(s):  
Kate Revill ◽  
Tim Wang ◽  
Anja Lachenmayer ◽  
Kensuke Kojima ◽  
Andrew Harrington ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Methylation Analysis ◽  
Suppressor Genes ◽  
Genome Wide

scholarly journals Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (8) ◽  
pp. 3937
Author(s):  
Colin F. Davenport ◽  
Tobias Scheithauer ◽  
Alessia Dunst ◽  
Frauke Sophie Bahr ◽  
Marie Dorda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Nanopore Sequencing ◽  
Sequencing Technology ◽  
Suppressor Genes ◽  
Genome Wide ◽  
A Genome

Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer.

scholarly journals Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

Cancers ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 8 ◽  
Author(s):  
Kwei-Yan Liu ◽  
Li-Ting Wang ◽  
Shih-Hsien Hsu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Chemical Sensor ◽  
Enzyme Level ◽  
Tumor Therapy ◽  
Tumor Formation ◽  
Current Evidence ◽  
Epigenetic Changes ◽  
Suppressor Genes

Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1.

scholarly journals Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma

Blood ◽  
2013 ◽  
Vol 122 (2) ◽  
pp. 219-226 ◽  
Author(s):  
Martin F. Kaiser ◽  
David C. Johnson ◽  
Ping Wu ◽  
Brian A. Walker ◽  
Annamaria Brioli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Drug Response ◽  
Tumor Biology ◽  
Methylation Analysis ◽  
Global Methylation ◽  
Suppressor Genes ◽  
Epigenetic Inactivation ◽  
Key Points

Key Points Epigenetic inactivation of tumor suppressor genes is associated with an unfavorable prognosis in multiple myeloma. Drug response and microenvironment interaction pathways are affected by epigenetic inactivation, linking tumor biology to prognosis.

scholarly journals Differential genome-wide array–based methylation profiles in prognostic subsets of chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 296-305 ◽  
Author(s):  
Meena Kanduri ◽  
Nicola Cahill ◽  
Hanna Göransson ◽  
Camilla Enström ◽  
Fergus Ryan ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Lymphocytic Leukemia ◽  
Chain Reaction ◽  
Global Methylation ◽  
Suppressor Genes ◽  
Genome Wide ◽  
Polymerase Chain

Abstract Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer; however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here, we analyzed the global methylation profiles in CLL, by applying high-resolution methylation microarrays (27 578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear factor-κB and mitogen-activated protein kinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data were validated for selected genes using methylation-specific polymerase chain reaction, quantitative reverse transcriptase–polymerase chain reaction, and bisulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by reinducing 4 methylated tumor suppressor genes (eg, VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2′-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis.

Abstract 840: Identification of novel colorectal tumor suppressor genes through genome-wide promoter hypermethylation analysis

2019 ◽  
Author(s):  
Sarah Bazzocco ◽  
Jose Higinio Dopeso ◽  
Águeda Martínez-Barriocanal ◽  
Estefanía Anguita ◽  
Rocio Nieto ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Promoter Hypermethylation ◽  
Colorectal Tumor ◽  
Suppressor Genes ◽  
Genome Wide

Mutation and Methylation Analysis of WWOX and CYLD on 16q; Potential Tumor Suppressor Genes in Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2473-2473
Author(s):  
Brian A. Walker ◽  
Matthew W. Jenner ◽  
Poala E. Leone ◽  
Nicholas J. Dickens ◽  
David C. Johnson ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Tumor Suppressor Genes ◽  
Uniparental Disomy ◽  
Myeloma Cell ◽  
Negative Regulator ◽  
Physical Interaction ◽  
Methylation Analysis ◽  
Suppressor Genes ◽  
Synonymous Mutations

Abstract We have shown that loss of heterozygosity (LOH) at 16q is an adverse prognostic marker when it occurs in combination with either t(4;14) translocation or del(17p). Using 500K Affymetrix mapping arrays we found that 16q was involved in translocations with the IgH locus, deleted, or had uniparental disomy (UPD). The deletion patterns led us to 2 regions at 16q12.1 and 16q21-q24.1, which contains 5 genes and is the location of the t(14;16) translocation. By integrating mapping and expression profiling data from presenting myeloma cases we were able to identify WWOX and CYLD as key genes deregulated in these regions. Both WWOX and CYLD are known tumor suppressor genes. WWOX is known to have a pro-apoptotic effect by participating in the TNF apoptotic pathway and via the direct physical interaction with p53 and p73. CYLD functions as a negative regulator of the NF-κB pathway as well as blocking the activation of cyclin D. WWOX is found to be methylated in other cancer tissues, whereas CYLD is frequently mutated. To determine mode of action of these genes in samples with LOH we performed mutation and methylation analysis on myeloma cell lines and pre-treatment patient samples. Variant transcripts of WWOX, which may act as dominant negatives to block the function of WWOX have been reported so we also determined the nature of these in the samples. Exons from WWOX and CYLD were PCR amplified from samples with LOH, as well as from samples with retention of heterozygosity, and sequenced directly. All differences to the consensus were checked against databases for known SNPs and mutations. Mutations in the tumor sample were confirmed by a repeat PCR, and mutations were also checked against peripheral blood DNA from the same patient to determine if these were acquired in the tumor. LOH of 16q was found in 2 out of 9 myeloma cell lines and additionally homozygous deletion of WWOX exons 5-8 in KMS11 cells was observed. cDNA analysis from these cell lines showed that KMS11 cells expressed variant 3, as could be expected, whereas the dominant transcript in other cell lines is variant 1. However, 2 cell lines also expressed an additional transcript (variant 4), which has previously been shown to act as a dominant-negative transcript. All pretreatment samples expressed the variant 1 transcript. 16 pretreatment samples with LOH were screened for mutations revealing 2 mutations in exon 9, one of which was non-synonymous. Methylation analysis of the WWOX locus is underway. Analysis of CYLD showed frequent mutation in cell lines with many synonymous and non-synonymous mutations, including several frame-shifts resulting in truncated products. Screening of 14 pretreatment samples with LOH at the CYLD locus revealed 2 mutations including a C>TT mutation in exon 11, which results in a frameshift and premature termination of translation. Alternative transcripts of CYLD are formed through splicing of exons 3 and 7. Both exon 3 variants were present but only the variant lacking exon 7 was present in myeloma cell lines. These data suggest that dysregulation of both WWOX and CYLD may be important in the pathogenesis of myeloma and contribute to the effect of del(16q) on patient survival.

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