Retinoic Acid Receptor β Silences Human Papillomavirus-18 Oncogene Expression by Induction of de Novo Methylation and Heterochromatinization of the Viral Control Region

Arce, Johanna De Castro; Göckel-Krzikalla, Elke; Rösl, Frank

doi:10.1074/jbc.m702870200

Cited by 22 publications

(16 citation statements)

References 76 publications

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“…Moreover, there even exists a cross-talk between cis-and transregulatory mechanisms because decreased transcriptional activity due to the presence/absence of a putative trans-repressor/activator can trigger epigenetic alterations (35,36). Such a situation marks promoter sequences for histone modifications and de novo methylation, finally leading to suppression of the respective gene (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells

et al. 2009

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We have investigated interferon-κ (IFN-κ) regulation in the context of human papillomavirus (HPV)-induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-κ was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-κ de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-κ expression. To prove the functional relevance of IFN-κ in building up an antiviral response, IFN-κ was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus-mediated cytolysis could be achieved. Reconstitution of IFN-κ was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-κ or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-κ, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-κ was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells. [Cancer Res 2009;69(22):8718-25]

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Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells

et al. 2009

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“…ChIP assays were performed as described previously [47]. Briefly, 1×10 7 of “444” cells were cross-linked with 1% formaldehyde for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Gene Expression of the Tumour Suppressor LKB1 Is Mediated by Sp1, NF-Y and FOXO Transcription Factors

Lützner

Arce²,

Rösl³

2012

PLoS ONE

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The serine/threonine kinase LKB1 is a tumour suppressor that regulates multiple biological pathways, including cell cycle control, cell polarity and energy metabolism by direct phosphorylation of 14 different AMP-activated protein kinase (AMPK) family members. Although many downstream targets have been described, the regulation of LKB1 gene expression is still poorly understood. In this study, we performed a functional analysis of the human LKB1 upstream regulatory region. We used 200 base pair deletion constructs of the 5′-flanking region fused to a luciferase reporter to identify the core promoter. It encompasses nucleotides −345 to +52 relative to the transcription start site and coincides with a DNase I hypersensitive site. Based on extensive deletion and substitution mutant analysis of the LKB1 promoter, we identified four cis-acting elements which are critical for transcriptional activation. Using electrophoretic mobility shift assays as well as chromatin immunoprecipitations, we demonstrate that the transcription factors Sp1, NF-Y and two forkhead box O (FOXO) family members FOXO3 and FOXO4 bind to these elements. Overexpression of these factors significantly increased the LKB1 promoter activity. Conversely, small interfering RNAs directed against NF-Y alpha and the two FOXO proteins greatly reduced endogenous LKB1 expression and phosphorylation of LKB1's main substrate AMPK in three different cell lines. Taken together, these results demonstrate that Sp1, NF-Y and FOXO transcription factors are involved in the regulation of LKB1 transcription.

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“…For example, it is now clear that the H-ras, N-ras and LAMP3 genes are activated in cervical tumors, whereas KAI1 and galectin-3 genes are inactivated [2,3,4,5]. In addition, it was found that the retinoic acid receptor beta gene is down-regulated in cervical tumors, whereas a gene for telomerase reverse transcriptase is up-regulated [6,7]. We found that the promoter of RASSF1A gene was methylated in squamous cervical carcinoma of Uigur women [8].…”

Section: Clinical Sample Collectionmentioning

confidence: 99%

Differential gene expression identified in Uigur women cervical squamous cell carcinoma by suppression subtractive hybridization

Pan

Chen²,

X³

et al. 2010

neo

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Cervical cancer is one of the most common gynecological cancers worldwide. Over the past decade, much progress has been made in understanding the genetic changes associated with the development and progression of cervical cancer. However, the precise mechanisms of cervical carcinogenesis in Uigur women remain unclear. To screen differential gene expression in squamous cell carcinoma (SCC) of the cervix in Uigur women, suppressive subtractive hybridization (SSH) was performed on the cervical squamous cell carcinoma and corresponding normal cervical tissues of a Uigur patient. Thus we were be able to find the genes that are related with cervical tumors of Uigur women. A total of 300 samples were subject to DNA sequencing analysis and 46 genes were found to express differentially in tumors compared with normal tissues. Of the 46 genes, 24 genes were up-regulated whereas 22 genes were down-regulated in cervical tumors. The expression profiles of 5 of the 46 genes were further confirmed in 15 other Uigur patients by semi-quantitative reverse-transcription polymerase chain reaction. Our results revealed that ACADVL, CEBPB, IFITM1 and DNAJC9 are involved in cervical carcinogenesis.

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Retinoic Acid Receptor β Silences Human Papillomavirus-18 Oncogene Expression by Induction of de Novo Methylation and Heterochromatinization of the Viral Control Region

Cited by 22 publications

References 76 publications

Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells

Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16–Positive Cells

Gene Expression of the Tumour Suppressor LKB1 Is Mediated by Sp1, NF-Y and FOXO Transcription Factors

Differential gene expression identified in Uigur women cervical squamous cell carcinoma by suppression subtractive hybridization

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