Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis

Shin, Myeong-Kyun; Balsitis, Scott; Brake, Tiffany; Lambert, Paul F.

doi:10.1158/0008-5472.can-08-3711

Cited by 64 publications

(56 citation statements)

References 40 publications

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“…In accordance with this finding SV40 LT and HPV E6 and E7 rescued the immortalization phenotype. All three viral oncoproteins negatively affect either p21 induction via inhibiting p53 and pRB or p21 function (12,42). Interestingly, HDAC1-deficient fibroblasts transformed with either SV40 LT or HPV16 E6/E7 show no signs of apoptosis as described for HDAC1-deficient human tumor cells (40).…”

Section: The Two Hdac1mentioning

confidence: 90%

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

Zupkovitz

Grausenburger

Brunmeir

et al. 2010

Molecular and Cellular Biology

128

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Histone deacetylases (HDACs) are chromatin-modifying enzymes that are involved in the regulation of proliferation, differentiation and development. HDAC inhibitors induce cell cycle arrest, differentiation, or apoptosis in tumor cells and are therefore promising antitumor agents. Numerous genes were found to be deregulated upon HDAC inhibitor treatment; however, the relevant target enzymes are still unidentified. HDAC1 is required for mouse development and unrestricted proliferation of embryonic stem cells. We show here that HDAC1 reversibly regulates cellular proliferation and represses the cyclin-dependent kinase inhibitor p21 in embryonic stem cells. Disruption of the p21 gene rescues the proliferation phenotype of HDAC1 ؊/؊ embryonic stem cells but not the embryonic lethality of HDAC1 ؊/؊ mice. In the absence of HDAC1, mouse embryonic fibroblasts scarcely undergo spontaneous immortalization and display increased p21 expression. Chromatin immunoprecipitation assays demonstrate a direct regulation of the p21 gene by HDAC1 in mouse embryonic fibroblasts. Transformation with simian virus 40 large T antigen or ablation of p21 restores normal immortalization of primary HDAC1؊/؊ fibroblasts. Our data demonstrate that repression of the p21 gene is crucial for HDAC1-mediated control of proliferation and immortalization. HDAC1 might therefore be one of the relevant targets for HDAC inhibitors as anticancer drugs.Acetylation of core histones is linked to the opening of chromatin and transcriptional activation. Modification of lysine residues by acetylation is thought to affect gene expression either by altering the affinity of histones to the DNA, or by creating binding sites for detector proteins that regulate chromatin accessibility. The antagonistic activities of two types of enzymes, histone acetyltransferases and histone deacetylases (HDACs), control the reversible acetylation state at the Nterminal tail of histones. HDACs catalyze the removal of the acetyl moieties from acetylated histones and other proteins and are in general associated with transcriptional repression (17). Based on their homologies with yeast deacetylases mammalian HDACs have been classified into Rpd3-like (class I), Hda1-like (class II), and Sir2-like (class III) enzymes (19). HDAC11 seems to represent a class (class IV) on its own.HDACs have been shown to regulate many important biological processes, including cell cycle progression, differentiation, and development. In agreement with this idea, HDAC inhibitor treatment leads to cell cycle arrest, differentiation, and apoptosis in cultured tumor cells and tumors in animal models. Therefore, several HDAC inhibitors are currently tested as antitumor drugs in clinical trials. A variety of HDAC inhibitors, which target class I and class II enzymes have been identified (33), and it has been shown that they exert their antiproliferative effects via transcriptional and nontranscriptional mechanisms (32). Treatment of untransformed cells with HDAC inhibitors triggers a G 2 checkpoint resulting in arr...

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Section: The Two Hdac1mentioning

confidence: 90%

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

Zupkovitz

Grausenburger

Brunmeir

et al. 2010

Molecular and Cellular Biology

128

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“…For example, E7 interacts with the pRbrelated "pocket proteins" p107 and p130, and the CDK inhibitors p21 CIP1 and p27 KIP1 (29)(30)(31). Inhibition of these key regulatory proteins for cell cycle arrest contributes to uncontrolled cellular proliferation and carcinogenesis (Fig.…”

Section: Introductionmentioning

confidence: 99%

Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications

Chung

Gillison

2009

Clinical Cancer Research

359

325

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with an annual incidence of approximately 400,000 worldwide. Although the principal risk factors for head and neck cancer remain tobacco and alcohol use, human papillomavirus (HPV) has recently been found to be etiologically associated with 20 to 25% of HNSCC, mostly in the oropharynx. HPV causes human cancers by expressing two viral oncoproteins, E6 and E7. These oncoproteins degrade and destabilize two major tumor suppressor proteins, p53 and pRb, through ubiquitination. Additional studies have shown that E6 and E7 can directly bind to multiple host proteins other than p53 and pRb (e.g., Bak and p21 Cip1 ), further contributing to genetic instability. However, expression of E6 and E7 alone is not sufficient for cellular transformation, and the additional genetic alterations necessary for malignant progression in the setting of virus-induced genomic instability are unknown. In addition to the etiological differences, HPV-positive cancers are clinically distinct when compared with HPV-negative cancers with regard to treatment response and survival outcome, with tumor HPV-positivity being a favorable prognostic biomarker. Further understanding of carcinogenesis and clinical behavior of HPV-positive cancers will improve disease prevention, patient care, and surveillance strategies for HNSCC patients. (Clin Cancer Res 2009;15(22):6758-62)

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“…21 However, some additional mechanisms may further modulate these effects. 22,23 Based on these observations, several studies propose p16 INK4a determined by immunohistochemistry in tumor tissue-derived material to be a useful surrogate marker for HPV-associated disease in HNSCC. 24,25 Exclusively, those HNSCCs being positive for both HPV DNA and p16 INK4a staining are expected to show the typical clinical HPV-related behavior, as mentioned earlier.…”

mentioning

confidence: 99%

p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

Hoffmann¹,

Ihloff²,

Görögh³

et al. 2010

Intl Journal of Cancer

120

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The causal role of human papillomaviruses (HPV) in squamous cell carcinogenesis of tonsillar cancers (TSCC) depends on the activity of the viral oncoproteins E6 and E7, leading to inactivation of the cellular tumor suppressor p53 and the retinoblastoma gene product pRb. Because of the negative feedback mechanisms, the pRb inactivation causes an increase of the inhibitor of the cyclin-dependent kinases p16 INK4a . In 39 TSCC specimens, genotyping based on the amplification of HPV DNA was carried out using PCR by applying HPV type-specific oligonucleotides. Subsequently, amplicons were hybridised with fluorescence-labeled complementary probes using the Southern blot technology. For HPV E6/E7 mRNA expression, Northern hybridization and RT-PCR were performed, and for p16 INK4a detection, immunohistochemistry was performed. With 21/39 (53%) HPV-positives, the detection rate is within the range that can be expected in TSCC. The E6/E7 oncogene mRNA was detectable in 11 cases, 10 of which showed positive signals after p16 INK4a staining. Albeit the small study group was investigated, the correlation of the HPV DNA status with the p16 INK4a expression was of statistical significance (p 5 0.02). Kaplan-Meier estimations revealed better survival outcome for patients with HPV-positive tumors with detectable E6/E7 mRNA and p16 INK4a overexpression (p 5 0.02, median observation time 29 months). As mRNA expression tests are not routinely available in many clinical diagnostic laboratories, and based on the high correlation of p16 INK4a staining with HPV E6/E7 mRNA expression, in conclusion we suggest for a deeper exploration for the use of p16 INK4a as a surrogate marker with the potential to impact the standard of care of HPV DNA-positive head and neck carcinomas.Malignant tumors of the upper aerodigestive tract account for $7% of all cancers worldwide, 1 with squamous cell carcinomas (SCCs) constituting the largest portion among the different tumor entities. 2 Even though a majority of SCCs of the head and neck (HNSCC) seems associated to etiologic factors as carcinogenetic substances in tobacco smoke and alcohol, 3 an increase of especially younger patients without reported misuse of these environmental factors in history has been recognized. 4 Therefore, an increase in knowledge of other factors such as the infection with human papillomaviruses (HPV) promoting carcinogenesis in especially the latter patient group gains in importance.Epidemiologic data demonstrate HPV DNA prevalences of about 20-30% concerning all anatomical tumor sites of the head and neck region, 4-6 with the SCC of the Waldeyer's tonsillar (squamous cell carcinogenesis of tonsillar cancers, TSCC) ring showing an HPV DNA-positive rate of up to 60% as particularly predestined for an infection with HPV. 4,5,7 Recent data from Sweden describe HPV DNA infections in tonsillar carcinomas in even up to 85% of the investigated patients. 8 HPV DNA-positive HNSCCs, again with accentuation of those derived from the Waldeyer's tonsillar ring, are considered as being ...

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Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis

Cited by 64 publications

References 40 publications

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications

p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

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Human Papillomavirus E7 Oncoprotein Overrides the Tumor Suppressor Activity of p21Cip1 in Cervical Carcinogenesis

Cited by 64 publications

References 40 publications

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation

Human Papillomavirus in Head and Neck Cancer: Its Role in Pathogenesis and Clinical Implications

p16INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

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p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer