Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies

Gallagher, William M.; Bergin, Orla; Rafferty, Máirín; Kelly, Zoe D.; Nolan, Ilse-Maria; Fox, Edward J.; Culhane, Aedín C.; McArdle, Linda; Fraga, Mario F.; Hughes, Linda; Currid, Caroline A.; O’Mahony, Fiona; Byrne, Aileen; Murphy, Alison; Moss, Catherine; McDonnell, Susan; Stallings, Raymond L.; Plumb, Jane A.; Esteller, Manel; Brown, Robert E.; Dervan, P.; Easty, David J.

doi:10.1093/carcin/bgi152

Cited by 108 publications

(95 citation statements)

References 46 publications

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“…To date, three different studies have reported microarray-based screening following treatment of uveal or cutaneous melanoma cell lines with the DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5AzadC) (van der Velden et al, 2003;Gallagher et al, 2005;Muthusamy et al, 2006) to find new TSGs silenced by methylation. Van der Velden et al, (van der Velden et al, 2003) identified 19 genes, including TIMP3 (tissue inhibitor of metalloproteinase 3) and TYRP1 (tyrosinase related protein 1), that were differentially expressed between a demethylated derivative clone of a primary uveal melanoma cell line and its untreated control.…”

Section: Discussionmentioning

confidence: 99%

“…Van der Velden et al, (van der Velden et al, 2003) identified 19 genes, including TIMP3 (tissue inhibitor of metalloproteinase 3) and TYRP1 (tyrosinase related protein 1), that were differentially expressed between a demethylated derivative clone of a primary uveal melanoma cell line and its untreated control. Gallagher et al, (2005) compared different highly tumorigenic derivative melanoma cell lines to their poorly tumorigenic parental cell lines (established from cutaneous superficial spreading melanomas). This group focused on TSPY, a Y chromosome specific gene normally expressed in the germ cells of the testis, which was hypermethylated in the derivative cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…However, many TSGs are not primarily inactivated through mutation or deletion, but rather through epigenetic changes such as promoter methylation, which down-regulate gene expression and lead to inactivation of TSGs which play a role in progression to malignancy (Rothhammer and Bosserhoff, 2007). Previous studies assessing genome-wide methylation in cutaneous melanoma following treatment with the DNA methyltransferase inhibitor 5-Aza-2-deoxycytidine (5AzadC) have identified TSPY, HOXB13 and SYK as novel TSGs (van der Velden et al, 2003;Gallagher et al, 2005;Muthusamy et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Bonazzi

Irwin

Hayward

2008

Genes Chromosomes & Cancer

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Tumor suppressor genes (TSGs) are sometimes inactivated by transcriptional silencing through promoter hypermethylation. To identify novel methylated TSGs in melanoma, we carried out global mRNA expression profiling on a panel of 12 melanoma cell lines treated with a combination of 5-Aza-2-deoxycytidine (5AzadC) and an inhibitor of histone deacetylase, Trichostatin A. Reactivation of gene expression after drug treatment was assessed using Illumina whole-genome microarrays. After qRT-PCR confirmation, we followed up 8 genes (AKAP12, ARHGEF16, ARHGAP27, ENC1, PPP1R3C, PPP1R14C, RARRES1, and TP53INP1) by quantitative DNA methylation analysis using mass spectrometry of base-specific cleaved amplification products in panels of melanoma cell lines and fresh tumors. PPP1R3C, ENC1, RARRES1, and TP53INP1, showed reduced mRNA expression in 35-59% of the melanoma cell lines compared to melanocytes and which was correlated with a high proportion of promoter methylation (>40-60%). The same genes also showed extensive promoter methylation in 6-25% of the tumor samples, thus confirming them as novel candidate TSGs in melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Bonazzi

Irwin

Hayward

2008

Genes Chromosomes & Cancer

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“…Increased TSPY expression occurs in testicular germ cell tumors 149 , as well as various types of somatic cancer, including melanoma 150 , prostate 151 and liver cancer 152 . Interestingly, while TSPY appears to exert a pro-oncogenic function, it has a homologue on the X chromosome, TSPX, which can be tumour suppressive 153 and protects from hepatitis B viral infection, a major risk for HCC 154 .…”

Section: B) Y Chromosomementioning

confidence: 99%

Sexual dimorphism in cancer

et al. 2016

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The incidence of many cancer types is significantly higher in the male than female populations, with associated differences in survival. Occupational and/or behavioral factors are well known underlying determinants. However, cellular/molecular differences between the two sexes are also likely to be important. We are focusing here on the complex interplay that sexual hormones and sex chromosomes can have in intrinsic control of cancer initiating cell populations, tumor microenvironment and systemic determinants of cancer development like the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment.3 Introduction (Epidemiology)

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“…The downregulation of the TSPY gene in melanoma progression is caused by promoter hypermethylation. 32 A recent study showed that sudden infant death with dysgenesis of the testes syndrome (SIDDT, OMIM no. #608800) was due to a frameshift mutation in the TSPYL1 gene, and this resulted in truncation at codon 169 leading to the loss of a region with high homology to the NAP domain.…”

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confidence: 99%

Gene silencing of TSPYL5 mediated by aberrant promoter methylation in gastric cancers

Jung

Park

Bang

et al. 2008

Laboratory Investigation

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DNA methylation is crucial for normal development, but gene expression altered by DNA hypermethylation is often associated with human diseases, especially cancers. The gene TSPYL5, encoding testis-specific Y-like protein, was previously identified in microarray screens for genes induced by the inhibition of DNA methylation and histone deacetylation in glioma cell lines. The TSPYL5 showed a high frequency of DNA methylation-mediated silencing in both glioma cell lines and primary glial tumors. We now report that TSPYL5 is also inactivated by DNA methylation and could be a putative epigenetic target gene in gastric cancers. We found that the expression of TSPYL5 mRNA was frequently downregulated and inversely correlated with DNA methylation in seven out of nine gastric cancer cell lines. TSPYL5 mRNA expression was also restored after treating with a DNA methyltransferase inhibitor. In primary gastric tumors, methylation-specific PCR results in 23 of the 36 (63.9%) cases revealed that the hypermethylation at CpG islands of the TSPYL5 was detectable at a high frequency. Furthermore, TSPYL5 suppressed the growth of gastric cancer cells as demonstrated by a colony formation assay. Thus, strong associations between TSPYL5 expression and hypermethylation were observed, and aberrant methylation at a CpG island of TSPYL5 may play an important role in development of gastric cancers. Epigenetic events are heritable modifications that regulate gene expression and can contribute to cancer development. 1 In particular, changes in DNA methylation are among the most common molecular alterations in human neoplasia, because the hypermethylation of a tumor suppressor gene at a promoter can lead to transcriptional silencing and the loss of gene function. 1-4 Gastric cancer is one of the most common malignancies in the world. 5 The promoter hypermethylation of multiple tumor suppressor genes resulting in gene silencing has been recognized as an important mechanism in gastrointestinal carcinogenesis. [6][7][8][9][10][11][12][13][14][15] In a previous study, TSPYL5 was identified as one of the genes induced after treatment with DNA methylation and histone deacetylation inhibitors in glioma cell lines using microarray analysis. 16 The TSPYL5 showed a high frequency of DNA methylation-mediated silencing in both glioma cell lines and primary glial tumors. A human TSPYL5 encoding testis-specific Y-like protein 5 (TSPYL5) is located on chromosome 8q22.1, but its role in human cancer has not been fully understood. The TSPYL5 protein is a member of TSPYL family that includes TSPYL1, TSPYL2, TSPYL3, TSPYL4, and TSPYL6. TSPYL proteins are also members of the nucleosome assembly protein (NAP) superfamily. The TSPYLs show sequence homology to NAPs, which have a highly conserved domain (the NAP domain) of approximately 180 amino acids. 17,18 The NAP domain is known to be required and sufficient for histone binding. 19 Members of the NAP family of proteins were identified in different systems and were classified with the NAPs based on their sequenc...

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Multiple markers for melanoma progression regulated by DNA methylation: insights from transcriptomic studies

Cited by 108 publications

References 46 publications

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Sexual dimorphism in cancer

Gene silencing of TSPYL5 mediated by aberrant promoter methylation in gastric cancers

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