Inverse Correlation between Cyclin A1 Hypermethylation and p53 Mutation in Head and Neck Cancer Identified by Reversal of Epigenetic Silencing

Tokumaru, Yutaka; Yamashita, Keishi; Osada, Motonobu; Nomoto, Shuji; Sun, Dong Il; Yan, Xuemin; Hoque, Mohammad O.; Westra, William H.; Califano, Joseph A.; Sidransky, David

doi:10.1158/0008-5472.can-04-0993

Cited by 128 publications

(156 citation statements)

References 28 publications

(32 reference statements)

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“…Pharmacological unmasking of esophageal squamous cell carcinoma and head and neck squamous cell carcinoma cell lines revealed that NmU expression was epigenetically silenced in these tumor types (126,127 ). These results were confirmed by analysis of clinical tumor and healthy patient samples, which showed that the NmU promoter is frequently hypermethylated in tumor tissue.…”

Section: Cancermentioning

confidence: 68%

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

Martínez

O’Driscoll

2015

Clinical Chemistry

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BACKGROUND Neuromedin U (NmU) belongs to the neuromedin family, comprising a series of neuropeptides involved in the gut–brain axis and including neuromedins B and C (bombesin-like), K (neurokinin B), L (neurokinin A or neurotensin), N, S, and U. CONTENT Although initially isolated from porcine spinal cord on the basis of their ability to induce uterine smooth muscle contraction, these peptides have now been found to be expressed in several different tissues and have been ascribed numerous functions, from appetite regulation and energy balance control to muscle contraction and tumor progression. NmU has been detected in several species to date, particularly in mammals (pig, rat, rabbit, dog, guinea pig, human), but also in amphibian, avian, and fish species. The NmU sequence is highly conserved across different species, indicating that this peptide is ancient and plays an important biological role. Here, we summarize the main structural and functional characteristics of NmU and describe its many roles, highlighting the jack-of-all-trades nature of this neuropeptide. SUMMARY NmU involvement in key processes has outlined the possibility that this neuropeptide could be a novel target for the treatment of obesity and cancer, among other disorders. Although the potential for NmU as a therapeutic target is obvious, the multiple functions of this molecule should be taken into account when designing an approach to targeting NmU and/or its receptors.

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Section: Cancermentioning

confidence: 68%

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

Martínez

O’Driscoll

2015

Clinical Chemistry

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“…The proposed mechanism of increased CCNA1 methylation is thought to be occurred in the interaction between E6/E7 and DNA methyltransferase on the CCNA1 promoter, leading to promote methylation and gene silencing. To this end, the function of cyclin A1 is likely to be as a tumor suppressor and involvement in the DNA repair mechanism (Muller-Tidow et al, 2004;Tokumaru et al, 2004;Kitkumthorn et al, 2006;Yanatatsaneejit et al, 2008). Consequently, in contrast to HPV infection involved in the early stage cervical cancer, cyclin A1 could likely lose DNA repair function, which may be crucial in the development of high-grade epithelial lesions.…”

Section: Discussionmentioning

confidence: 99%

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

Chujan

Kitkumthorn²,

Siriangkul³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: From our previous study, we established that cyclin A1 (CCNA1) promoter methylation is strongly correlated with multistep progression of HPV-associated cervical cancer, suggesting potential use as a diagnostic maker of disease. Objectives: The purpose of the present study was to assess the prevalence of CCNA1 promoter methylation in residual cervical cells isolated from liquid-based cytology that underwent hrHPV DNA screening for cervical cancer, and then to evaluate this marker for diagnostic accuracy using parameters like sensitivity, specificity, predictive values and likelihood ratio. Methods: In this retrospective study, histopathology was used as the gold standard method with specimens separated into the following groups: negative (n=31), lowgrade squamous intraepithelial lesions (LSIL, n=34) and high-grade squamous intraepithelial lesions or worse (HSIL+, n=32). The hrHPV was detected by Hybrid Capture 2 (HC2) and CCNA1 promoter methylation was examined by CCNA1 duplex methylation specific PCR. Results: The results showed the frequencies of CCNA1 promoter methylation were 0%, 5.88% and 83.33%, while the percentages of hrHPV were 66.67%, 82.35% and 100% in the negative, LSIL and HSIL+ groups, respectively. Although hrHPV infection showed high frequency in all three groups, it could not differentiate between the different groups and grades of precancerous lesions. In contrast, CCNA1 promoter methylation clearly distinguished between negative/LSIL and HSIL+, with high levels of all statistic parameters. Conclusion: CCNA1 promoter methylation is a potential marker for distinguishing between histologic negative/LSIL and HSIL+using cervical cytology samples.

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“…UCHL1 silencing in cancers was first discovered in pancreatic cancers by chemical genomic screening, 23 and then in head and neck cancers. 12 Recently, UCHL1 methylation was shown to be associated with a poor prognosis in esophageal squamous cell carcinomas. 24 In contrast, in pancreatic, colorectal and lung cancers, overexpression of UCHL1 protein was reported, [25][26][27] and its overexpression was associated with a poor prognosis in pancreatic and colorectal cancers.…”

Section: Discussionmentioning

confidence: 99%

Silencing of the UCHL1 gene in human colorectal and ovarian cancers

Okochi‐Takada

Nakazawa

Wakabayashi

et al. 2006

Intl Journal of Cancer

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Aberrant DNA methylation is associated with many types of human cancers. To identify genes silenced in human colorectal cancers, we performed a microarray analysis for genes whose expression was induced by treatment of HCT116 human colon cancer cells with a demethylating agent, 5-aza-2 0 -deoxycitidine (5-aza-dC). Seven known genes were identified as being upregulated (8-fold) and expressed at more than twice as high as the average level. Among these was the UCHL1 gene (also known as PGP9.5), which is involved in regulation of cellular ubiquitin levels. A dense CpG island in its promoter region was completely methylated in HCT116 cells, and no mRNA was detected. 5-Aza-dC treatment of HCT116 cells induced dose-dependent demethylation of the CpG island, and restored UCHL1 mRNA and protein expression. UCHL1 silencing was observed in 11 of 12 human colorectal cancer cell lines, and its methylation was detected in 8 of 17 primary colorectal cancers. Further, UCHL1 silencing was observed in 6 of 13 ovarian cancer cell lines, and its methylation was detected in 1 of 17 primary ovarian cancers. These results showed that UCHL1 is inactivated in human colorectal and ovarian cancers by its promoter methylation, and suggest that disturbance of cellular ubiquitin levels is present.

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Inverse Correlation between Cyclin A1 Hypermethylation and p53 Mutation in Head and Neck Cancer Identified by Reversal of Epigenetic Silencing

Cited by 128 publications

References 28 publications

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

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

Silencing of the UCHL1 gene in human colorectal and ovarian cancers

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