An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single‐base resolution methylome and hydroxymethylome

Han, Yingxin; Ji, Liyan; Guan, Yanfang; Ma, Mengya; Li, Pansong; Xue, Yinge; Zhang, Yinxin; Huang, Wanqiu; Gong, Yuhua; Xie, Hong; Zhou, Boping; Wang, Jiayin; Wang, Junwen; Han, Jinghua; Deng, Yuliang; Yi, Xin; Gao, Fei; Huang, Jian

doi:10.1002/ctm2.498

Cited by 8 publications

(9 citation statements)

References 92 publications

(165 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of this mechanism during cervical carcinogenesis may be more critical during early stages of carcinogenesis, as others have reported elevated levels of TET1 during cervical premalignancy [63,64]. Even thought a lot of studies suggest a substantial increase in the global methylation of HPV-positive tumors [65][66][67][68][69], bisulfite sequencing is not a robust method in differentiating between methylation and hydroxymethylation. Moreover, aberrant DNA methylation/demethylation may vary among specific loci, despite overall patterns.…”

Section: Discussionmentioning

confidence: 99%

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer

Panayiotou

Eftychiou

Patera

et al. 2023

Preprint

View full text Add to dashboard Cite

The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in HPV-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4 driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate transcription by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer

Panayiotou

Eftychiou

Patera

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The importance of this mechanism during cervical carcinogenesis may be more critical during early stages of carcinogenesis, as we and others have reported elevated levels of TET1 during cervical premalignancy. 34,35 Even though a lot of studies suggest a substantial increase in the global methylation of HPV-positive tumors, [43][44][45][46][47] bisulfite sequencing is not a robust method in differentiating between methylation and hydroxymethylation. Moreover, aberrant DNA methylation/demethylation may vary among specific loci, despite overall patterns.…”

Section: Discussionmentioning

confidence: 99%

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

Panayiotou,

Eftychiou,

Patera

et al. 2023

Journal of Medical Virology

View full text Add to dashboard Cite

The Octamer‐binding transcription factor‐4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post‐embryonic re‐expression is inadequately understood. In cervical cancer, Oct4 expression is higher in human papillomavirus (HPV)‐related than HPV‐unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4‐transcriptional output and Oct4‐related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4‐protein interactions in cervical cancer cells via computational analyses and Mass Spectrometry and reveal that Methyl‐binding proteins (MBD2 and MBD3), are determinants of Oct4‐driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re‐expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate Oct4 re‐expression and global transcriptional patterns by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.

show abstract

“…These six genes had been reported in some studies. One study analyzed the epigenomic landscape and identify RPS6KA6 as potential biomarker for CC, which is significantly correlated with the overall survival of CC [ 22 ]. Another study constructed a six-gene prognostic model, including PTTG1, that could become the new promising target for the cervical cancer treatment [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

A cellular senescence-related genes model allows for prognosis and treatment stratification of cervical cancer: a bioinformatics analysis and external verification

Yang,

An,

et al. 2023

Aging

View full text Add to dashboard Cite

Background: Cervical cancer (CC) is highly lethal and aggressive with an increasing trend of mortality for females. Molecular characterization-based methods hold great promise for improving the diagnostic accuracy and for predicting treatment response. Methods: The mRNAs expression data of CC patients and cellular senescence-related genes were obtained from the Cancer Genome Atlas (TCGA) and CellAge databases, respectively. Differentially expressed genes (DEGs) of senescence related genes between tumor and normal tissues were used for Least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model. Univariate and LASSO regression analyses were applied to establish a predictive nomogram. The performance of the nomogram were evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index (C-index), and calibration curve. GSE44001 and GSE52903 were used for external validation. Results: We established a cellular senescence-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of CC patients in the TCGA database. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better overall survival (OS, P =2.021e-05). The area under the ROC curve (AUC) of this model was 0.743 for OS. Multivariate analysis found that the 6-gene risk signature (HR=3.166, 95%CI: 1.660-6.041, P<0.001) was an independent risk factor for CC patients. We then designed an OS-associated nomogram that included the risk signature and clinicopathological factors. The AUC reached 0.860 for predicting 5-year OS. The nomogram showed excellent consistency between the predictions and actual survival observations. Two external GEO validations were corresponding to the gene expression pattern in TCGA. Conclusions: Our results suggested a six-senescence related signature and established a prognostic nomogram that reliably predicted the overall survival for CC. These findings may be beneficial to personalized treatment and medical decision-making.

show abstract

An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single‐base resolution methylome and hydroxymethylome

Cited by 8 publications

References 92 publications

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer

A paradigm for post-embryonic Oct4 re-expression: E7-induced hydroxymethylation regulates Oct4 expression in cervical cancer

A paradigm for post‐embryonic Oct4 re‐expression: E7‐induced hydroxymethylation regulates Oct4 expression in cervical cancer

A cellular senescence-related genes model allows for prognosis and treatment stratification of cervical cancer: a bioinformatics analysis and external verification

Contact Info

Product

Resources

About