Loss of expression of the growth inhibitory gene GADD45γ, in human pituitary adenomas, is associated with CpG island methylation

Bahar, Adil; Bicknell, John E.; Simpson, David J.; Clayton, Richard N.; Farrell, William E.

doi:10.1038/sj.onc.1207193

Cited by 86 publications

(60 citation statements)

References 34 publications

(47 reference statements)

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“…Moreover, loss and downregulated expression of CDH13 mRNA and E-cadherin protein were significantly associated with hypermethylation of CDH13 and CDH1, respectively. Thus, our data, along with previous studies, [15][16][17][18][19][20] suggest that epigenetic alterations are common hallmarks of pituitary tumorigenesis. The aberrant expression of H-cadherin and E-cadherin and their DNA promoter hypermethylation may play an important role in pituitary tumor pathogenesis.…”

Section: Discussionsupporting

confidence: 86%

“…14 There is increasing evidence of aberrant promoter methylation of TSGs in the pathogenesis of pituitary adenomas, although some of them are tumor subtype specific. [15][16][17][18][19][20] The p16/CDKN2A and RB1 gene methylation with tumor subtype specificity were described in pituitary tumors. [15][16][17] Preferential loss of death-associated protein kinase (DAPK) expression in invasive pituitary tumors has been reported to be associated with CpG island methylation.…”

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confidence: 99%

“…18 Methylation-associated gene silencing of the GADD45g gene, a negative regulator of cell growth, also has been found in human pituitary tumors and a mouse pituitary tumor cell line AtT20. 19 Most recently, hypermethylation of RASS-F1A and resultant alteration of RASSF1A expression have been detected in pituitary adenomas of all types. 20 These results promoted us to investigate the roles of CDH13 and CDH1 in human pituitary tumorigenesis and tumor behavior.…”

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confidence: 99%

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Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

et al. 2007

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The gene products of CDH13 and CDH1, H-cadherin and E-cadherin, respectively, play a key role in cell-cell adhesion. Inactivation of the cadherin-mediated cell adhesion system caused by aberrant methylation is a common finding in human cancers, indicating that the CDH13 and CDH1 function as tumor suppressor and invasion suppressor genes. In this study, we analyzed the expression of H-cadherin mRNA and E-cadherin protein in 5 normal pituitary tissues and 69 primary pituitary adenomas including all major types by quantitative real-time RT-PCR (qRT-PCR) and immunohistochemistry, respectively. Reduced expression of H-cadherin was detected in 54% (28/52) of pituitary tumors and was significantly associated with tumor aggressiveness (Po0.05). E-cadherin expression was lost in 30% (21 of 69) and significantly reduced in 32% (22 of 69) of tumors. E-cadherin expression was significantly lower in grade II, III, and IV than in grade I adenomas (P ¼ 0.015, P ¼ 0.029, and P ¼ 0.01, respectively). Using methylation-specific PCR (MSP), promoter hypermethylation of CDH13 and CDH1 was detected in 30 and 36% of 69 adenomas, respectively, but not in 5 normal pituitary tissues. Methylation of CDH13 was observed more frequently in invasive adenomas (42%) than in non-invasive adenomas (19%) (Po0.05) and methylation of CDH1 was more frequent in grade IV adenomas compared with grade I adenomas (Po0.05). Methylation of either CDH13 or CDH1 was identified in 35 cases (51%) and was more frequent in grade IV invasive adenomas than in grade I non-invasive adenomas (Po0.05 and Po0.05, respectively). Downregulation of expression was correlated with promoter hypermethylation in CDH13 and CDH1. In conclusion, the tumor-specific downregulation of expression and methylation of CDH13 and CDH1, alone or in combination, may be involved in the development and invasive growth of pituitary adenomas.

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Section: Discussionsupporting

confidence: 86%

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confidence: 99%

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confidence: 99%

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Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

et al. 2007

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“…These studies have identified transcripts that show loss or significantly reduced expression in primary tumours relative to post-mortem normal pituitaries. Using this technique, the Klibanski group identified growth arrest and DNA damage-inducible gene (GADD45g) and maternally expressed gene 3 (MEG3) transcripts as differentially expressed in pituitary tumours (Zhang et al 2002(Zhang et al , 2003 and subsequent studies showed that loss of GADD45g and of the MEG3 isoform, MEG3a, transcript was associated with methylation of their CpG islands (Bahar et al 2004a,b, Zhao et al 2005. Both of these genes were also shown to fulfil the criteria of bona fide tumour suppressors since enforced expression in cell lines including those in a pituitary lineage was responsible for growth inhibition and/or reduction in colony forming efficiency.…”

Section: Methylation and Gene Silencing: Differential Display Approachesmentioning

confidence: 99%

Pituitary tumours: all silent on the epigenetics front

Dudley¹,

Revill²,

Clayton³

et al. 2009

Journal of Molecular Endocrinology

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Investigation of the epigenome of sporadic pituitary tumours is providing a more detailed understanding of aberrations that characterise this tumour type. Early studies, in this and other tumour types adopted candidate-gene approaches to characterise CpG island methylation as a mechanism responsible for or associated with gene silencing. However, more recently, investigators have adopted approaches that do not require a priori knowledge of the gene and transcript, as example differential display techniques, and also genome-wide, array-based approaches, to 'uncover' or 'unmask' silenced genes. Furthermore, through use of chromatin immunoprecipitation as a selective enrichment technique; we are now beginning to identify modifications that target the underlying histones themselves and that have roles in genesilencing events. Collectively, these studies provided convincing evidence that change to the tumour epigenome are not simply epiphenomena but have functional consequences in the context of pituitary tumour evolution. Our ability to perform these types of studies has been and is increasingly reliant upon technological advances in the genomics and epigenomics arena. In this context, other more recent advances and developing technologies, and, in particular, next generation or flow cell re-sequencing techniques offer exciting opportunities for our future studies of this tumour type.

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“…1,2 Hypermethylation of gene promoter regions has been implicated in the inactivation of several genes, including p16/ CDKN2A, RB1, DAPK, GADD45g, RASSF1A, E-cadherin, H-cadherin, Ikaros, and FGFR2. [3][4][5][6][7][8][9][10][11] GSTP1 encodes glutathione-S-transferase-p, a member of a family of enzymes, the glutathione-S-transferases (GSTs) that function as dimers composed of subunits from five main classes: a, m, p, s, and y. GSTs are phase 2 enzymes that catalyze the conjugation of glutathione with electrophilic and hydrophobic compounds including carcinogens, natural toxins, and exogenous drugs. [12][13][14] GSTs are believed to play an important role in protecting cells from cytotoxic and carcinogenic agents.…”

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Reduction of GSTP1 expression by DNA methylation correlates with clinicopathological features in pituitary adenomas

et al. 2008

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p-Class glutathione-S-transferase (GSTP1) located on chromosome 11q13 encodes a phase II metabolic enzyme that detoxifies reactive electrophilic intermediates. GSTP1 plays an important role in the protecting cells from cytotoxic and carcinogenic agents and is expressed in normal tissues at variable levels in different cell types. Altered GSTP1 activity and expression have been reported in many tumors and this is largely due to GSTP1 DNA hypermethylation. The role of GSTP1 in pituitary tumorigenesis has not been investigated. In this study, we evaluated the GSTP1 expression level and GSTP1 DNA methylation status in a series of pituitary adenomas. Using immunohistochemistry, we identified expression of GSTP1 in all of the various normal hormoneproducing adenohypophysial cell types. In pituitary adenomas, loss or reduced expression of GSTP1 was detected in 27 of 53 tumors (50.9%). Expression of GSTP1 was significantly lower in invasive adenomas than in noninvasive adenomas (Po0.05). Using methylation-specific polymerase chain reaction (MS-PCR), GSTP1 DNA promoter hypermethylation was detected in adenomas (38 of 53, 71.7%) but not in normal tissues. GSTP1 methylation was more frequent in grade II, III, and IV tumors (66.7, 85, and 83%, respectively) than in grade I tumors (33%, Po0.05). In addition, the frequency of GSTP1 methylation was higher in invasive tumors (85%) than in noninvasive tumors (59%; Po0.05). Methylation status correlated with significant downregulation of GSTP1 expression; the frequency of GSTP1 methylation was higher in tumors with reduced-GSTP1 expression (85%) than in tumors with normal or high GSTP1 expression (54%; Po0.05).These data indicate that GSTP1 inactivation through CpG hypermethylation is common in pituitary adenomas and may contribute to aggressive pituitary tumor behavior.

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Loss of expression of the growth inhibitory gene GADD45γ, in human pituitary adenomas, is associated with CpG island methylation

Cited by 86 publications

References 34 publications

Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas

Pituitary tumours: all silent on the epigenetics front

Reduction of GSTP1 expression by DNA methylation correlates with clinicopathological features in pituitary adenomas

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