Limits...
Coordinated activation of candidate proto-oncogenes and cancer testes antigens via promoter demethylation in head and neck cancer and lung cancer.

Smith IM, Glazer CA, Mithani SK, Ochs MF, Sun W, Bhan S, Vostrov A, Abdullaev Z, Lobanenkov V, Gray A, Liu C, Chang SS, Ostrow KL, Westra WH, Begum S, Dhara M, Califano J - PLoS ONE (2009)

Bottom Line: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported.We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS.Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

ABSTRACT

Background: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC.

Methodology/principal findings: We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells.

Conclusions/significance: Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.

Show MeSH

Related in: MedlinePlus

Gene expression and demethylation correlation.(a) Shows the gene expression correlation p-value matrix for the coexpression for each gene pair across all tumors. This comparison shows the correlation of each gene pair in 49 head and neck tumors. (b) Gene pair expression p-value correlation matrix for 80 NSCLC. Of note C19ORF28 is not tiled on this array platform. (c) Analysis of promoter regions for the genes. Shown is a phylogram of our promoters of interest based on ClustalW analysis after multiple sequence alignment. The region of significant homology is shown after sequence alignment and E statistics from EMBL-EBI's PromoterWise comparison. (d) Promoter hypomethylation (QUMSP) correlation p-value matrix for HNSCC (25 tumors). (e) Promoter hypomethylation (QUMSP) correlation p-value matrix for NSCLC (13 tumors).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2654921&req=5

pone-0004961-g006: Gene expression and demethylation correlation.(a) Shows the gene expression correlation p-value matrix for the coexpression for each gene pair across all tumors. This comparison shows the correlation of each gene pair in 49 head and neck tumors. (b) Gene pair expression p-value correlation matrix for 80 NSCLC. Of note C19ORF28 is not tiled on this array platform. (c) Analysis of promoter regions for the genes. Shown is a phylogram of our promoters of interest based on ClustalW analysis after multiple sequence alignment. The region of significant homology is shown after sequence alignment and E statistics from EMBL-EBI's PromoterWise comparison. (d) Promoter hypomethylation (QUMSP) correlation p-value matrix for HNSCC (25 tumors). (e) Promoter hypomethylation (QUMSP) correlation p-value matrix for NSCLC (13 tumors).

Mentions: During these analyses, we quickly noted that transcriptional upregulation via promoter hypomethylation tended to occur synchronously in a subset of tumors. In our cohort of 49 primary HNSCC assayed via expression array analysis, we constructed a matrix of Pearson's correlation coefficients between the expression levels of each target (Figure 6A). For our nine target genes, significant clustering of increased expression was noted within the MAGEA family of genes. H19 was not included because of its absence on the U133A platform. A separate cluster of associated overexpression was noted for TKTL1, GRIN1, and GPR17. From NSCLC expression data derived from the expO datasets we created similar matrices to examine correlations between individual genes. We noted that MAGEA family expression and H19 expression showed highly significant correlations in individual NSCLC (see Figure 6B). In contrast, there were no target-target correlations for NSCLC expression of the other cluster (TKTL1, GRIN1, and GPR17) that exhibited coordinated expression in HNSCC.


Coordinated activation of candidate proto-oncogenes and cancer testes antigens via promoter demethylation in head and neck cancer and lung cancer.

Smith IM, Glazer CA, Mithani SK, Ochs MF, Sun W, Bhan S, Vostrov A, Abdullaev Z, Lobanenkov V, Gray A, Liu C, Chang SS, Ostrow KL, Westra WH, Begum S, Dhara M, Califano J - PLoS ONE (2009)

Gene expression and demethylation correlation.(a) Shows the gene expression correlation p-value matrix for the coexpression for each gene pair across all tumors. This comparison shows the correlation of each gene pair in 49 head and neck tumors. (b) Gene pair expression p-value correlation matrix for 80 NSCLC. Of note C19ORF28 is not tiled on this array platform. (c) Analysis of promoter regions for the genes. Shown is a phylogram of our promoters of interest based on ClustalW analysis after multiple sequence alignment. The region of significant homology is shown after sequence alignment and E statistics from EMBL-EBI's PromoterWise comparison. (d) Promoter hypomethylation (QUMSP) correlation p-value matrix for HNSCC (25 tumors). (e) Promoter hypomethylation (QUMSP) correlation p-value matrix for NSCLC (13 tumors).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654921&req=5

pone-0004961-g006: Gene expression and demethylation correlation.(a) Shows the gene expression correlation p-value matrix for the coexpression for each gene pair across all tumors. This comparison shows the correlation of each gene pair in 49 head and neck tumors. (b) Gene pair expression p-value correlation matrix for 80 NSCLC. Of note C19ORF28 is not tiled on this array platform. (c) Analysis of promoter regions for the genes. Shown is a phylogram of our promoters of interest based on ClustalW analysis after multiple sequence alignment. The region of significant homology is shown after sequence alignment and E statistics from EMBL-EBI's PromoterWise comparison. (d) Promoter hypomethylation (QUMSP) correlation p-value matrix for HNSCC (25 tumors). (e) Promoter hypomethylation (QUMSP) correlation p-value matrix for NSCLC (13 tumors).
Mentions: During these analyses, we quickly noted that transcriptional upregulation via promoter hypomethylation tended to occur synchronously in a subset of tumors. In our cohort of 49 primary HNSCC assayed via expression array analysis, we constructed a matrix of Pearson's correlation coefficients between the expression levels of each target (Figure 6A). For our nine target genes, significant clustering of increased expression was noted within the MAGEA family of genes. H19 was not included because of its absence on the U133A platform. A separate cluster of associated overexpression was noted for TKTL1, GRIN1, and GPR17. From NSCLC expression data derived from the expO datasets we created similar matrices to examine correlations between individual genes. We noted that MAGEA family expression and H19 expression showed highly significant correlations in individual NSCLC (see Figure 6B). In contrast, there were no target-target correlations for NSCLC expression of the other cluster (TKTL1, GRIN1, and GPR17) that exhibited coordinated expression in HNSCC.

Bottom Line: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported.We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS.Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

ABSTRACT

Background: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC.

Methodology/principal findings: We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells.

Conclusions/significance: Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.

Show MeSH
Related in: MedlinePlus