Genetic and epigenetic changes of HPV16 in cervical cancer differentially regulate E6/E7 expression and associate with disease progression

Mazumder, Dipanjana; Singh, Ratnesh; Mitra, Soma; Dutta, Sankhadeep; Chakraborty, Chitraleema; Basu, Partha; Mondal, Ranajit Kumar; Roychoudhury, Susanta; Panda, Chinmay Kumar

doi:10.1016/j.ygyno.2011.08.004

Cited by 58 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies also reported a very low methylation frequency in cervical dysplasia (28,30,32,33,36). This contrasts with the work of Mazumder and collaborators (31), who describe methylated CpG in 50% of LSIL-HSIL. These authors used microdissected histological samples to select tissue with at least 60% abnormal epithelial cells, an approach that is not well suited for routine use.…”

Section: Hpv16 E2bs Hrm-pcr Is a Reliable Methods For Methylation Assementioning

confidence: 79%

“…For example, Mazumder and collaborators (31) showed that in addition to integration, the absence of HPV16 LCR methylation was associated with a poor prognosis in cancer patients. In our series, all the cancer samples were early-stage tumors (Federation of Gynecology and Obstetrics [FIGO] stage I or II), which are known to have a better outcome than late-stage tumors.…”

Section: Hpv16 E2bs Hrm-pcr Is a Reliable Methods For Methylation Assementioning

confidence: 99%

“…Some studies reported decreased E2BS methylation during lesion progression (30)(31)(32) or a trend of a lower risk of incident precancerous and cancerous lesions for patients with high E2BS methylation (33,34). On the contrary, methylation of the five CpGs located in the E2BS1 and E2BS2 and Sp1-binding site (Sp1BS) has frequently been associated with cervical cancer (28,29,(35)(36)(37)(38), and a gradual increase in methylation during lesion progression toward cancer has been reported in some studies (29,36,37,39).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Methylation of Human Papillomavirus Type 16 CpG Sites at E2-Binding Site 1 (E2BS1), E2BS2, and the Sp1-Binding Site in Cervical Cancer Samples as Determined by High-Resolution Melting Analysis–PCR

et al. 2013

View full text Add to dashboard Cite

Certain Alphapapillomavirus species classified as high-risk human papillomaviruses (HR-HPVs) have been recognized as the etiologic factors of invasive cervical carcinoma worldwide (1, 2). HR-HPV infections are frequent in young women but they are generally transient, with an estimated mean duration of incident infection of 16 months (3). Only persistent HR-HPV infections are associated with an increased risk of developing high-grade cervical lesions or cancer of the cervix (4-6). Persistent HR-HPV infections may be associated with microscopic abnormalities called low-grade squamous intraepithelial lesions (LSIL). These LSIL present a high rate of regression following HPV clearance but may progress toward high-grade squamous intraepithelial lesions (HSIL) if HR-HPV infection persists. Upon diagnosis, HSIL are treated mostly by excisional procedures to avoid the risk of progression toward invasive cancer (for a review, see reference 7).Among the HR-HPV types, HPV16 exhibits the highest persistence rate (8). Moreover, HPV16 is associated with an increased risk of developing precancerous and cancerous lesions (9) and is considered the most carcinogenic PV in humans (10). This is probably why HPV16 prevalence increases with the severity of cervical lesions (11), reaching 61% in invasive cervical carcinoma worldwide (12).HPV-associated carcinogenesis requires the continuous overexpression of the two main viral oncoproteins E7 and E6, which interact with many cellular proteins leading to the induction and the maintenance of a transformed phenotype in infected cells (for a review, see reference 13). E7 and E6 expression is regulated by the viral E2 protein through the early promoter (named p97 for HPV16) located in the long control region (LCR) of the PV genome. This promoter harbors four specific E2-binding sites (E2BSs) sharing the consensus sequence 5=-ACCG(N) 4 15). The three sites proximal to the TATA box have been shown to be involved in E2-mediated repression of the promoter activity, and E2BS1 and E2BS2 are probably the main sites to achieve this effect (for a review, see reference 16). From a mechanistic point of view, the binding of E2 to E2BS1 and E2BS2 induces a displacement of transcription activators, such as specificity protein 1 (Sp1) and TATA binding protein (TBP), from their binding sites, leading to a repression of E7 and E6 expression from the early promoter (17, 18). HR-HPV DNA integration has been described as a key step in the carcinogenesis process, since it generally results in the disruption of the E2 open reading frame (ORF) (19,20).Epigenetic alterations, and particularly aberrant DNA methylation, are frequently associated with tumor progression. Methylation of DNA mainly occurs on cytosines located in CpG dinucle-

show abstract

Section: Hpv16 E2bs Hrm-pcr Is a Reliable Methods For Methylation Assementioning

confidence: 79%

Section: Hpv16 E2bs Hrm-pcr Is a Reliable Methods For Methylation Assementioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Methylation of Human Papillomavirus Type 16 CpG Sites at E2-Binding Site 1 (E2BS1), E2BS2, and the Sp1-Binding Site in Cervical Cancer Samples as Determined by High-Resolution Melting Analysis–PCR

et al. 2013

View full text Add to dashboard Cite

show abstract

“…2 and 7). In cervical cancer, E6 and E7 expression has been linked to hypermethylation and tumor invasiveness (44)(45)(46). Although uterine cervical cancer and HNSCC are distinct diseases, demethylating the host genome in HPV-associated tumors may begin to reverse the fundamental steps of HPV-driven carcinogenesis and remove protective measures that allow the expression of viral genes.…”

Section: Discussionmentioning

confidence: 99%

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Biktasova

Hajek

Sewell

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: DNA methylation in human papillomavirus-associated (HPV þ ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV þ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV þ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV þ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV þ HNSCC. classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%). In contrast, genetic alterations in these genes are extremely rare in the HPV þ subset (TP53, 3%; CDKN2A, 0%; ref. 6), which instead is associated with a mutational signature typical of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) antiviral proteins (6, 11-13). In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18). A majority of HNSCC patients are treated with radiation and platin-based chemotherapy, which is associated with deleterious and lifelong side-effects. Despite the relatively good prognosis associated with HPV þ HNSCC, 25%-30% of patients with HPV-positive tumors experience recurrent or metastatic disease, for which treatment options are limited. The molecular and epigenetic differences between HPV þ and HPV À tumors provide an opportunity for therapies that exploit the interaction of the HPV genome and host that result in hypermethylation of cancer cell genomes. 5-Azacytidine (5-aza)

show abstract

“…It includes hyper-and hypomethylation of the DNA, altered chromatin structure due to histone tail modifications and deregulated miRNA expression that can either activate oncogenes or silence tumor suppressor genes which may induce genomic instability and promote carcinogenesis [83] . HPV genome-related alterations include methylation of HPV E2 binding sites, HPV E6, E7, and long control regions [84][85][86][87][88] . It has been found that genes encoded by oncogenic viruses such as HPV, Epstein-Barr virus, SV40, hepatitis B virus, and many others synthesize proteins which can interact with host epigenetic machinery leading to its deregulation.…”

Section: Hpv and Other Pathogenic Infections Epigenetics And Cervicmentioning

confidence: 99%

Epigenomics, Pharmacoepigenomics, and Personalized Medicine in Cervical Cancer

Kabekkodu

Chakrabarty

Ghosh

et al. 2017

Public Health Genomics

View full text Add to dashboard Cite

Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events. Recent studies have also mapped these epigenetic modification and pathways leading to carcinogenesis. Discovery of drugs that target proteins/enzymes in the epigenetic pathways may provide better therapeutic opportunities, and identification of such modulators for DNA methylation, histone modifications, and expression of noncoding RNAs for several cancer types is underway. In this review, we provide a detailed description of recent developments in the field of epigenetics and its impact on personalized medicine to manage cervical cancer.

show abstract

Genetic and epigenetic changes of HPV16 in cervical cancer differentially regulate E6/E7 expression and associate with disease progression

Cited by 58 publications

References 50 publications

Methylation of Human Papillomavirus Type 16 CpG Sites at E2-Binding Site 1 (E2BS1), E2BS2, and the Sp1-Binding Site in Cervical Cancer Samples as Determined by High-Resolution Melting Analysis–PCR

Methylation of Human Papillomavirus Type 16 CpG Sites at E2-Binding Site 1 (E2BS1), E2BS2, and the Sp1-Binding Site in Cervical Cancer Samples as Determined by High-Resolution Melting Analysis–PCR

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Epigenomics, Pharmacoepigenomics, and Personalized Medicine in Cervical Cancer

Contact Info

Product

Resources

About