Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma

Uchida, Daisuke; Nm, Begum; Almofti, Ammar; Kawamata, Hitoshi; Yoshida, Hideo; Sato, Mitsunobu

doi:10.1038/sj.bjc.6602004

Cited by 45 publications

(42 citation statements)

References 34 publications

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“…In this regard, it is interesting to note that a certain proportion of human salivary gland tumors express elevated levels of ErbB2 (34)(35)(36)(37). Conversely, 14-3-3σ is downregulated through hypermethylation in certain salivary gland tumors (38). Another study demonstrated that a mutant polyomavirus unable to sequester 14-3-3 proteins failed to develop salivary tumors, which were characteristic of the wild-type polyomavirus (39).…”

Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammmentioning

confidence: 99%

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3σ allele lose expression of the remaining 14-3-3σ allele, which is associated with epigenetic methylation of the 14-3-3σ locus. In addition to accelerated tumor onset, in a mouse mammary tumor virusdriven ErbB2 tumor model, loss of 14-3-3σ results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3σ is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.siGNiFicaNce: 14-3-3σ has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3σ in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks. Cancer Discovery; 2(1); 68-81.

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Section: Discussion Loss Of 14-3-3s Is a Critical Event In Erbb2 Mammmentioning

confidence: 99%

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Chen

Zuo

et al. 2012

Cancer Discovery

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“…The CpG island of the 14-3-3 s gene in salivary gland adenoid cystic carcinoma cells was found to be methylated inside the exon, whereas HSG cells showed very a limited pattern of hemimethylation in the 14-3-3 s gene. Methylation occurring at CpG sites inside the exon, a coding region, has been shown to significantly reduce the expression of 14-3-3 s. 36 Therefore, it is highly likely that internal methylation within an exon, a coding region, can affect the DNA-binding activity of transcription factors; moreover, inhibition of this methylation is likely to correlate with increased expression of the relevant gene. We found that any demethylation occurring at 14 methylated CG sites was sufficient to increase the transcriptional activity of the M3R gene, resulting in increased M3R protein expression and increased M3R function.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Shin

Jin

Hwang

et al. 2015

Laboratory Investigation

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Muscarinic receptors, particularly the type 3 subtype (M3R), have an important role in exocrine secretion. M3R normally function in HSG cells originated from human submandibular gland ducts, but not in A253 and SGT cells, derived from human submandibular carcinoma and salivary gland adenocarcinoma. However, the underlying mechanism of this suppression has remained elusive. In this study, we examined whether M3R function is suppressed by epigenetic modulation of the receptor. To this end, we investigated the mRNA transcript and protein levels of the M3R using reverse transcriptase-PCR, western blot, and confocal microscopy analyses. Global DNA methylation assays, methylation-specific PCR, and bisulfite sequencing were also performed to understand the epigenetic status of the M3R CpG island. We found that A253 cells expressed all subtypes of muscarinic receptors, except M3R, on the mRNA level. However, treatment of cells with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), a DNA-demethylating agent, increased the expression levels of both M3R mRNA transcript and protein in proportion to the incubation period. 5-Aza-CdR completely restored the carbacholinduced calcium response, which was not observed in untreated A253 cells. In untreated A253 cells, all CG pairs from the 1st to 14th were methylated and 5-Aza-CdR treatment demethylated one of the methylated CG pairs. We also examined the methylation pattern of M3R CpG island in human cancer tissue. Interestingly, the result was very similar to those of A253 cells. All CG pairs in M3R CpG island were also methylated. Another salivary gland tumor cell line, SGT, also showed the similar methylation pattern, heavy methylation in M3R CpG island. It is concluded that CpG island in M3R is hypermethylated in cancer cell lines and human cancer. Our results further suggest that 5-Aza-CdR could potentially be used to restore the function of M3R, suppressed in some cancer cell types. Epigenetic regulation by CpG methylation has an important role in tumorigenesis, and is also crucial to mounting a successful response to cancer therapy. CpG islands in DNA are methylated de novo in a tissue-specific manner, and the patterns of methylation are fixed in subsequent cell divisions by methyltransferase activity. 1 Recent studies have indicated that hypermethylation of CpG islands within the promoter and 5 0 regions of genes is an important epigenetic mechanism for suppressing gene expression. 2-4 DNA hypermethylation may directly affect the basal transcriptional machinery by altering the secondary structure of DNA and inducing chromosome remodeling through methyl group-binding proteins and histone deacetylase, thereby leading to transcriptional repression. 5 5-Aza-2 0 -deoxycytidine (5-Aza-CdR, decitabine) is a prodrug that has been shown to be phosphorylated, and thus activated, by deoxytidine kinase. 5-Aza-CdR is a nucleotide analog that is incorporated into DNA, where it irreversibly inactivates DNA methyltransferase (DNMT); 5-Aza-CdR is also an S-phase-specific agent. 6 The cytosine DNMT gen...

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“…Nishimine et al 28 29 and Uchida et al analyzed the promoter methylation status of the 14-3-3 sigma gene in 8 ACCs and found a high frequency of promoter methylation. 30 Our current study is the first to investigate the promoter methylation status of RASSF1A, DAPK, and MGMT and in a substantially larger sample size than any of the previous studies.…”

Section: Ink4amentioning

confidence: 99%

Promoter methylation of p16^INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma

El‐Naggar

2005

Cancer

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BACKGROUNDPromoter methylation is a common mechanism of inactivation of tumor suppressor genes in multiple tumor types. However, little is known about its role in the development of adenoid cystic carcinoma of the salivary gland (ACC). In the current study, the authors investigated whether promoter methylation is common in ACC and whether it may influence ACC development.METHODSThe promoter methylation status of the genes p16INK4a, RASSF1A, DAPK, and MGMT, which are important in cell growth regulation, apoptosis, and DNA repair, was determined in tissue sections of tumor samples from 60 patients with ACC using methylation‐specific polymerase chain reaction. The association between methylation status and patients' clinical and pathologic characteristics were assessed.RESULTSOf the 60 tumors, DNA methylation of the p16INK4a promoter was detected in 28 tumors (47%); the respective values DNA methylation of the RASSF1A, DAPK, and MGMT promoters were 25 tumors (42%), 16 tumors (27%), and 4 tumors (7%), respectively. Forty‐six tumors (77%) had DNA methylation in ≥ 1 of the 4 promoters, 20 tumors (33%) had DNA methylation in ≥ 2 promoters, 6 tumors (10%) had DNA methylation in ≥ 3 promoters, and 1 tumor (2%) had DNA methylation in all 4 promoters. RASSF1A promoter methylation was more frequent in high‐grade tumors than in low‐grade tumors (P = 0.009), in advanced‐stage tumors (P = 0.008), and in tumors with metastasis (P = 0.005).CONCLUSIONSPromoter methylation of p16INK4a, RASSF1A, and DAPK was common in ACC, and it is possible that such methylation may influence the development of ACC. The high frequency of RASSF1A promoter methylation in high‐grade tumors and in tumors with metastasis suggested a role for this gene in the progression of ACC. Cancer 2005. © 2005 American Cancer Society.

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Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma

Cited by 45 publications

References 34 publications

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Promoter methylation of p16^INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma

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Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma

Cited by 45 publications

References 34 publications

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Epigenetic modulation of the muscarinic type 3 receptor in salivary epithelial cells

Promoter methylation of p16INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma

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Promoter methylation of p16^INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma