Aberrant DNA Methylation of Two Tumor Suppressor Genes, p14ARF and p15INK4b , after Chronic Occupational Exposure to Low Level of Benzene

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

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ABERRANT DNA METHYLATION AS A CANCER-INDUCING MECHANISM

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev.pharmtox.45.120403.095832 ◽

2005 ◽

Vol 45 (1) ◽

pp. 629-656 ◽

Cited By ~ 331

Author(s):

Manel Esteller

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Cpg Island ◽

Gene Mutations ◽

Promoter Hypermethylation ◽

Dna Methyltransferases ◽

Tumor Type ◽

Suppressor Genes ◽

Aberrant Dna Methylation

Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16INK4a, BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation “invades” the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.

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Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation

Cancer Letters ◽

10.1016/j.canlet.2012.03.016 ◽

2012 ◽

Vol 322 (2) ◽

pp. 204-212 ◽

Cited By ~ 23

Author(s):

Mizuho Kikuyama ◽

Hideyuki Takeshima ◽

Takayuki Kinoshita ◽

Eriko Okochi-Takada ◽

Mika Wakabayashi ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Suppressor Genes ◽

Novel Approach ◽

Aberrant Dna Methylation

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Targeting DNA methylation for treating triple-negative breast cancer

Pharmacogenomics ◽

10.2217/pgs-2019-0078 ◽

2019 ◽

Vol 20 (16) ◽

pp. 1151-1157 ◽

Cited By ~ 3

Author(s):

Jia Yu ◽

Jacqueline Zayas ◽

Bo Qin ◽

Liewei Wang

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Tumor Suppressor ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Triple Negative ◽

Suppressor Genes ◽

Dna Methyltransferase Inhibitors

Triple-negative breast cancer (TNBC) accounts for 15–20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

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DNA Methylation Changes Following 5-Azacitidine Treatment in Patients with Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v114.22.2791.2791 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2791-2791

Author(s):

Huong Thi Thanh Tran ◽

Hee Nam Kim ◽

Yeo-Kyeoung Kim ◽

Jae-Sook Ahn ◽

Il-Kwon Lee ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Dna Methyltransferase ◽

Conflicts Of Interest ◽

Control Group ◽

Disease Pathogenesis ◽

Suppressor Genes ◽

Clinical Responses ◽

Dependent Probe

Abstract Abstract 2791 Poster Board II-767 Gene silencing by promoter methylation is as potent as functional inactivating of tumor suppressor genes by mutations. DNA methyltransferase inhibitor, 5-azacytidine (AC) and 5-aza-2 -deoxycitidine (DAC), which is proved to be effective in myelodysplastic syndromes (MDS) can induce re-expression in cancer; however their mechanism remains controversial. 25 tumor suppressor genes by MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification) were analyzed in 44 MDS patients treated Vidaza® (5-azacitidine, AC). Hypermethylation of at least one gene was detected in 9/44 patients (20.5%), including four genes CDKN2B, FHIT, ESR1 and IGSF4. Interestingly, of 9 hypermethylated patients, 8 patients showed demethylation in concordance with their clinical responses after three to five cycles AC treatment. Lack or decrease methylation was observed in four patients with hematological improvements. Persistence methylation was observed in four others who became AML transformation or no response after treatment, especially reinforcing methylated gene in a case progressed to leukemia later. Our study also founds out IGSF4 gene hypermethylation in MDS as a first report. Additionally, mRNA expression of CDKN2B, IGSF4, and ESR1 in MDS were significantly lower than those in the control group (p < 0.05). Our results suggest that the methylation changes of specific genes contributes to disease pathogenesis and might present a molecular marker that can be used to monitor the efficacy of AC treatment in MDS. Disclosures: No relevant conflicts of interest to declare.

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Ambient PM exposure and DNA methylation in tumor suppressor genes: a cross-sectional study

Particle and Fibre Toxicology ◽

10.1186/1743-8977-8-25 ◽

2011 ◽

Vol 8 (1) ◽

pp. 25 ◽

Cited By ~ 45

Author(s):

Lifang Hou ◽

Xiao Zhang ◽

Letizia Tarantini ◽

Francesco Nordio ◽

Matteo Bonzini ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

Suppressor Genes

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Chrysin Modulates Aberrant Epigenetic Variations and Hampers Migratory Behavior of Human Cervical (HeLa) Cells

Frontiers in Genetics ◽

10.3389/fgene.2021.768130 ◽

2022 ◽

Vol 12 ◽

Author(s):

Ritu Raina ◽

Abdulmajeed G. Almutary ◽

Sali Abubaker Bagabir ◽

Nazia Afroze ◽

Sharmila Fagoonee ◽

...

Keyword(s):

Dna Methylation ◽

Tumor Suppressor ◽

Histone Modification ◽

Hela Cells ◽

Tumor Suppressor Genes ◽

Methylation Status ◽

Global Dna Methylation ◽

Dependent Manner ◽

Suppressor Genes ◽

Protein Levels

Purpose: Plant-derived phytochemicals have shown epigenetic modulatory effect in different types of cancer by reversing the pattern of DNA methylation and chromatin modulation, thereby restoring the function of silenced tumor-suppressor genes. In the present study, attempts have been made to explore chrysin-mediated epigenetic alterations in HeLa cells.Methods: Colony formation and migration assays followed by methylation-specific PCR for examining the methylation status of CpG promoters of various tumor-suppressor genes (TSGs) and the expression of these TSGs at the transcript and protein levels were performed. Furthermore, global DNA methylation; biochemical activities of DNA methyltransferases (DNMTs), histone methyl transferases (HMTs), histone deacetylases (HDACs), and histone acetyl transferases (HATs) along with the expression analysis of chromatin-modifying enzymes; and H3 and H4 histone modification marks analyses were performed after chrysin treatment.Results: The experimental analyses revealed that chrysin treatment encourages cytostatic behavior as well as inhibits the migration capacity of HeLa cells in a time- and dose-dependent manner. Chrysin reduces the methylation of various tumor-suppressor genes, leading to their reactivation at mRNA and protein levels. The expression levels of various chromatin-modifying enzymes viz DNMTs, HMTs, HDACs, and HATS were found to be decreased, and H3 and H4 histone modification marks were modulated too. Also, reduced global DNA methylation was observed following the treatment of chrysin.Conclusion: This study concludes that chrysin can be used as a potential epigenetic modifier for cancer treatment and warrants for further experimental validation.

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Hypermethylated promoters of tumor suppressor genes were identified in Crohn’s disease patients

Intestinal Research ◽

10.5217/ir.2019.00105 ◽

2020 ◽

Vol 18 (3) ◽

pp. 297-305

Author(s):

Tae-Oh Kim ◽

Yu Kyeong Han ◽

Joo Mi Yi

Keyword(s):

Dna Methylation ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Tumor Suppressor ◽

Environmental Factors ◽

Tumor Suppressor Genes ◽

Bisulfite Sequencing ◽

Sequencing Analysis ◽

Gene Promoters ◽

Suppressor Genes

Background/Aims: Overwhelming evidence suggests that inflammatory bowel disease (IBD) is caused by a complicated interplay between the multiple genes and abnormal epigenetic regulation in response to environmental factors. It is becoming apparent that epigenetic factors are significantly associated with the development of the disease. DNA methylation remains the most studied epigenetic modification, and hypermethylation of gene promoters is associated with gene silencing.Methods: DNA methylation alterations may contribute to the many complex diseases development by regulating the interplay between external and internal environmental factors and gene transcriptional expression. In this study, we used 15 tumor suppressor genes (TSGs), originally identified in colon cancer, to detect promoter methylation in patients with Crohn’s disease (CD). Methylation specific polymerase chain reaction and bisulfite sequencing analyses were performed to assess methylation level of TSGs in CD patients.Results: We found 6 TSGs (sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4) are robustly hypermethylated in CD patient samples. Bisulfite sequencing analysis confirmed the methylation levels of the sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4 promoters in the representative CD patient samples.Conclusions: In this study, the promoter hypermethylation of the TSGs observed indicates that CD exhibits specific DNA methylation signatures with potential clinical applications for the noninvasive diagnosis of IBD and the prognosis for patients with IBD.

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