CCNA1 Promoter Methylation: a Potential Marker for Grading Papanicolaou Smear Cervical Squamous Intraepithelial Lesions

Chujan, Suthipong; Kitkumthorn, Nakarin; Siriangkul, Sumalee; Mutirangura, Apiwat

doi:10.7314/apjcp.2014.15.18.7971

Cited by 25 publications

(32 citation statements)

References 33 publications

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“…Consistent with previous findings, the CCNA1 and TERT promoter regions showed significantly increased methylation (24–28% increase in β, p < 0.004) in NIKS-16 cells compared to NIKS cells (Table S3) 10, 13, 14, 23 . However, NIKS-18 cells did not show consistent changes in CCNA1 and TERT promoter methylation.…”

Section: Resultssupporting

confidence: 91%

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High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes

Cicchini

Blumhagen

Westrich

et al. 2017

Sci Rep

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Human papillomavirus (HPV) infection distinctly alters methylation patterns in HPV-associated cancer. We have recently reported that HPV E7-dependent promoter hypermethylation leads to downregulation of the chemokine CXCL14 and suppression of antitumor immune responses. To investigate the extent of gene expression dysregulated by HPV E7-induced DNA methylation, we analyzed parallel global gene expression and DNA methylation using normal immortalized keratinocyte lines, NIKS, NIKS-16, NIKS-18, and NIKS-16∆E7. We show that expression of the MHC class I genes is downregulated in HPV-positive keratinocytes in an E7-dependent manner. Methylome analysis revealed hypermethylation at a distal CpG island (CGI) near the HLA-E gene in NIKS-16 cells compared to either NIKS cells or NIKS-16∆E7 cells, which lack E7 expression. The HLA-E CGI functions as an active promoter element which is dramatically repressed by DNA methylation. HLA-E protein expression on cell surface is downregulated by high-risk HPV16 and HPV18 E7 expression, but not by low-risk HPV6 and HPV11 E7 expression. Conversely, demethylation at the HLA-E CGI restores HLA-E protein expression in HPV-positive keratinocytes. Because HLA-E plays an important role in antiviral immunity by regulating natural killer and CD8+ T cells, epigenetic downregulation of HLA-E by high-risk HPV E7 may contribute to virus-induced immune evasion during HPV persistence.

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Section: Resultssupporting

confidence: 91%

“…Consistently, the HPV E7-DNMT1 complex induces hypermethylation of the tumor suppressor cyclin A1 ( CCNA1 ) promoter, an epigenetic marker strongly correlated with HPV-associated malignancy 13, 14 . Further, our recent work has revealed that the chemokine CXCL14 is significantly downregulated by E7-directed promoter hypermethylation 15 .…”

Section: Introductionmentioning

confidence: 86%

High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes

Cicchini

Blumhagen

Westrich

et al. 2017

Sci Rep

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“…We have previously reported that methylation of the CCNA1 promoter was largely elevated in ~93% of cervical cancer cases, whereas the promoter remains unmethylated in normal counterparts . In addition, other studies recommended that the CCNA1 promoter methylation status be used as the optimal molecular marker for distinguishing between normal/low‐grade squamous intraepithelial neoplasia and high‐grade squamous intraepithelial neoplasia cancer lesions . Moreover, we also observed a significant correlation between the integrated form of HPV infection and CCNA1 promoter methylation .…”

supporting

confidence: 62%

“…(17) In addition, other studies recommended that the CCNA1 promoter methylation status be used as the optimal molecular marker for distinguishing between normal ⁄ low-grade squamous intraepithelial neoplasia and high-grade squamous intraepithelial neoplasia cancer lesions. (18,19) Moreover, we also observed a significant correlation between the integrated form of HPV infection and CCNA1 promoter methylation. (20) Interestingly, the study by Weiss et al found a significant correlation between HPV-related head and neck cancer and CCNA1 methylation.…”

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confidence: 54%

Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation

et al. 2015

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Human papillomavirus (HPV) oncoproteins drive distinctive promoter methylation patterns in cancer. However, the underlying mechanism remains to be elucidated. Cyclin A1 (CCNA1) promoter methylation is strongly associated with HPV-associated cancer. CCNA1 methylation is found in HPV-associated cervical cancers, as well as in head and neck squamous cell cancer. Numerous pieces of evidence suggest that E7 may drive CCNA1 methylation. First, the CCNA1 promoter is methylated in HPV-positive epithelial lesions after transformation. Second, the CCNA1 promoter is methylated at a high level when HPV is integrated into the human genome. Finally, E7 has been shown to interact with DNA methyltransferase 1 (Dnmt1). Here, we sought to determine the mechanism by which E7 increases methylation in cervical cancer by using CCNA1 as a gene model. We investigated whether E7 induces CCNA1 promoter methylation, resulting in the loss of expression. Using both E7 knockdown and overexpression approaches in SiHa and C33a cells, our data showed that CCNA1 promoter methylation decreases with a corresponding increase in expression in E7 siRNA-transfected cells. By contrast, CCNA1 promoter methylation was augmented with a corresponding reduction in expression in E7-overexpressing cells. To confirm whether the binding of the E7–Dnmt1 complex to the CCNA1 promoter induced methylation and loss of expression, ChIP assays were carried out in E7-, del CR3-E7 and vector control-overexpressing C33a cells. The data showed that E7 induced CCNA1 methylation by forming a complex with Dnmt1 at the CCNA1 promoter, resulting in the subsequent reduction of expression in cancers. It is interesting to further explore the genome-wide mechanism of E7 oncoprotein-mediated DNA methylation.

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“…In both cervical and endometrial cancer, specific genes involved in various pathways are known to be methylated. In cervical cancer, these genes include tumor protein p73, fragile histidine triad (FHIT), death-associated protein kinase 1 and PRDI-BF and RIZ domain containing 14 in the apoptotic pathway; cyclin A1 (CCNA1) and double C2-like domain β in the cell cycle; adenomatous polyposis coli (APC) and secreted frizzled-related protein (SFRP) in the Wnt/β-catenin pathway; Fanconi anemia, complementation group F, O-6-methylguanine-DNA methyltransferase, human MutL homolog 1 (hMLH1) and CCNA1 in DNA repair; FHIT, retinoic acid receptor-β and myelin and lymphocyte in the cell growth pathway; and CXC chemokine receptor 4 and cell adhesion molecule 1, which are involved in cell adhesion (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In endometrial cancer, the following genes are methylated: APC, caspase-8, checkpoint with forkhead-associated and ring finger, E-cadherin, hMLH1, p73, progesterone receptor, phosphatase and tensin homologue deleted on chromosome 10, Ras association domain family 1 isoform A and thrombospondin 2 .…”

Section: Introductionmentioning

confidence: 99%

Recent findings on epigenetic gene abnormalities involved in uterine cancer

Yanokura

Banno

Kobayashi

et al. 2017

Molecular and Clinical Oncology

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Abstract. Selective aberrant genetic effects that do not depend on abnormal DNA sequences are referred to as epigenetic abnormalities and are involved in carcinogenesis. In uterine cancer, various genes involved in apoptosis, cell cycle, DNA repair, cell proliferation and cell adhesion are abnormally methylated, resulting in gene silencing. Reversal of such epigenetic abnormalities in cancer cells is a potential strategy for cancer therapy, and studies on epigenetic abnormalities and treatment methods in uterine cancer are in progress. These include the evaluation of 5-hydroxymethylcytosine, which is present in cancer tissues at lower levels compared with those in normal tissues, as a prognostic marker in cervical cancer; combination therapy with 5-azacytidine and cisplatin; combination treatment focusing on tumor necrosis factor-related apoptosis-inducing ligand in cervical cancer; studies focusing on DNA mismatch repair in endometrial cancer; and use of a demethylating agent to reactivate tumor suppressor genes and inhibit tumor proliferation. Detection of epigenetic changes using biomarkers may be used for histological classification, evaluation of disease progression and identification of compounds that are able to modulate epigenetic changes and may be useful for uterine cancer treatment.

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CCNA1 Promoter Methylation: a Potential Marker for Grading Papanicolaou Smear Cervical Squamous Intraepithelial Lesions

Cited by 25 publications

References 33 publications

High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes

High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes

Human papillomavirus type 16 E7 oncoprotein mediates CCNA1 promoter methylation

Recent findings on epigenetic gene abnormalities involved in uterine cancer

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