Impact of viral and host DNA methylations on HPV16-related cervical cancer pathogenesis

Epigenetic alterations within human papillomavirus (HPV) and host cellular genomes are known to occur during cervical carcinogenesis. Our objective was to analyse the influence of (1) methylation within two immunostimulatory CpG motifs within HPV16 E6 and E7 genes around the viral late promoter and their correlation, if any, with expression deregulation of host receptor (TLR9) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) and (2) global DNA methylation levels within CpGs of the repetitive Alu sequences, on cervical cancer (CaCx) pathogenesis. Significantly higher proportions of CaCx samples portrayed methylation in immunostimulatory CpG motifs, compared to HPV16-positive non-malignant samples, with cases harbouring episomal HPV16 showing decreased methylation compared to those with viral integration. A significant linear trend of TLR9 upregulation was recorded in the order of HPV–negative controls < HPV16-positive non-malignant samples < HPV16-positive CaCx cases. TLR9 upregulation in cases with episomal HPV16 was again higher among those with non-methylated immunostimulatory CpG motifs. Comparison of cases with HPV–negative controls revealed that DNMT3A was significantly downregulated only among integrated cases, DNMT3B was significantly overexpressed among both categories of cases, although at variable levels, while DNMT1 failed to show any deregulated expression among the cases. Global host DNA hypomethylation, also showed a significant linear increasing trend through the progressive CaCx development stages mentioned above and was most prominently higher among cases with episomal HPV16 as opposed to viral integration. Thus, HPV16 and host methylations appear to influence CaCx pathogenesis, with differential molecular signatures among CaCx cases with episomal and integrated HPV16.

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The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases

Cells ◽

10.3390/cells10020266 ◽

2021 ◽

Vol 10 (2) ◽

pp. 266

Author(s):

Shin-ichiro Takebayashi ◽

Tyrone Ryba ◽

Kelsey Wimbish ◽

Takuya Hayakawa ◽

Morito Sakaue ◽

...

Keyword(s):

Dna Replication ◽

Temporal Order ◽

Expression System ◽

Embryonic Stem ◽

Replication Timing ◽

Dna Methyltransferases ◽

Dna Hypomethylation ◽

Transcriptional Changes ◽

A Cell ◽

Genomic Regions

Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various Dnmt-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape.

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Association of cervical carcinogenesis risk with HPV16 E6 and E7 variants in the Taizhou area, China

BMC Cancer ◽

10.1186/s12885-021-08531-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mei-Zhen Dai ◽

Yi Qiu ◽

Xing-Hong Di ◽

Wei-Wu Shi ◽

Hui-Hui Xu

Keyword(s):

Cervical Cancer ◽

Cervical Carcinogenesis ◽

Chi Square ◽

Major Health Problem ◽

Hpv16 E6 ◽

Exact Test ◽

Chi Square Test ◽

E6 And E7

Abstract Background Human papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China. Methods We aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher’s exact test. Results In this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1–3 (European) sublineages (OR = 2.69, 95% CI = 1.04–6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer. Conclusion These data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China.

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miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer

10.21203/rs.2.9472/v1 ◽

2019 ◽

Author(s):

Hui Wang ◽

Hui Hu ◽

Zhenzhao Luo ◽

Shuiyi Liu ◽

Wangze Wu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Invasion ◽

Tumor Suppressor Genes ◽

Target Gene ◽

Migration And Invasion ◽

Caski Cell ◽

Hpv16 E6 ◽

Invasion And Migration ◽

C33a Cell ◽

And Migration

Abstract The abnormal expression of HPV16 E6/E7 activates oncogenes and/or inactivates tumor suppressor genes, resulting in the selective growth and malignant transformation of cancer cells. miR-4454 was selected by sequencing due to its abnormal high expression in HPV16 E6/E7 positive CaSki cell compared with HPV16 E6/E7 negative C33A cell. Overexpression of miR-4454 enhances cervical cancer cell invasion and migration. ABHD2 and NUDT21 is identified as a target gene of miR-4454.The effects of ABHD2 and NUDT21 on migration and invasion of CaSki and C33A cells were determined. The dual luciferase and RT-qPCR assays confirmed that miR-4454 might regulate its targets ABHD2 and NUDT21 to promote the proliferation, invasion and migration, whereas, inhibit the apoptosis in CaSki and C33A cells.

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Epigenetic modifications and human pathologies: cancer and CVD

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003952 ◽

2010 ◽

Vol 70 (1) ◽

pp. 47-56 ◽

Cited By ~ 64

Author(s):

Susan J. Duthie

Keyword(s):

Dna Methylation ◽

Human Cancer ◽

Dna Methyltransferases ◽

Water Soluble ◽

Leafy Vegetables ◽

Dna Hypomethylation ◽

Human Diet ◽

Human Colon Cancer ◽

Increased Risk ◽

Risk Of Cancer

Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD.

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HPV16 E6 oncoprotein‐induced upregulation of lncRNA GABPB1‐AS1 facilitates cervical cancer progression by regulating miR‐519e‐5p/Notch2 axis

The FASEB Journal ◽

10.1096/fj.202000762r ◽

2020 ◽

Vol 34 (10) ◽

pp. 13211-13223

Author(s):

Rongying Ou ◽

Mingfen Lv ◽

Xuan Liu ◽

Jiangmin Lv ◽

Jinduo Zhao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Hpv16 E6 ◽

E6 Oncoprotein

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Exploring the p53 connection of cervical cancer pathogenesis involving north-east Indian patients

PLoS ONE ◽

10.1371/journal.pone.0238500 ◽

2020 ◽

Vol 15 (9) ◽

pp. e0238500

Author(s):

Mohammad Aasif Khan ◽

Diptika Tiwari ◽

Anita Dongre ◽

Sadaf ◽

Saad Mustafa ◽

...

Keyword(s):

Cervical Cancer ◽

East Indian ◽

North East ◽

Cancer Pathogenesis ◽

Indian Patients

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Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents

Hematology ◽

10.1182/asheducation-2017.1.460 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 460-469 ◽

Cited By ~ 2

Author(s):

Olatoyosi Odenike

Keyword(s):

Critical Appraisal ◽

Stem Cell Transplant ◽

Clinical Investigation ◽

Dna Methyltransferases ◽

Cell Transplant ◽

Dna Hypomethylation ◽

New Agents ◽

Hypomethylating Agent ◽

The Us ◽

History Of

Abstract In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanucleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients who relapse after, or do not respond to, hypomethylating agent therapy, the outcome is dismal, and new agents and approaches that have the potential to alter the natural history of these diseases are desperately needed. Allogeneic stem cell transplant is the only known potentially curative approach in MDS, but its applicability has been limited by the advanced age of patients and attendant comorbidities. There is now an increasing array of new agents under clinical investigation in MDS that aim to exploit our expanding understanding of molecular pathways that are important in the pathogenesis of MDS. This review focuses on a critical appraisal of novel agents being evaluated in higher-risk MDS that go beyond the conventional hypomethylating agent therapies approved by the US Food and Drug Administration.

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Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

Cancers ◽

10.3390/cancers12030764 ◽

2020 ◽

Vol 12 (3) ◽

pp. 764 ◽

Cited By ~ 4

Author(s):

Wa Zhang ◽

David Klinkebiel ◽

Carter J. Barger ◽

Sanjit Pandey ◽

Chittibabu Guda ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Genomic Instability ◽

Human Cancer ◽

Disease Free Survival ◽

Gene Expression Signature ◽

Dna Methyltransferases ◽

Dna Demethylation ◽

Dna Hypomethylation ◽

Proliferation Markers

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis.

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