Dataset Information

Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells.

ABSTRACT: Treatment of advanced stage ovarian cancer continues to be challenging due to acquired drug resistance and lack of early stage biomarkers. Genes identified to be aberrantly expressed at the 3q26.2 locus (i.e. SnoN/SkiL) have been implicated in ovarian cancer pathophysiology. We have previously shown that SnoN expression is increased in advanced stage ovarian cancers and alters cellular response to arsenic trioxide (As2O3).We now demonstrate increased DNA copy number levels (TCGA data) of phospholipid scramblase 1 (PLSCR1, located at 3q23) whose transcript expression in ovarian cell lines is highly correlated with SnoN mRNA. Interestingly, SnoN can modulate PLSCR1 mRNA levels in the absence/presence of interferon (IFN-2?). Both IFN-2? and As2O3 treatment can modulate PLSCR1 mRNA levels in ovarian carcinoma cells. However, SnoN siRNA does not lead to altered PLSCR1 protein implicating other events needed to modulate its protein levels. In addition, we report that PLSCR1 can modulate aspects of the As2O3 cellular response.Our findings warrant further investigation into the role of PLSCR1 in ovarian cancer development and chemoresistance.

SUBMITTER: Kodigepalli KM

PROVIDER: S-EPMC3644492 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells.

Kodigepalli Karthik M KM Anur Pavana P Spellman Paul P Sims Peter J PJ Nanjundan Meera M

Molecular cancer 20130426

<h4>Background</h4>Treatment of advanced stage ovarian cancer continues to be challenging due to acquired drug resistance and lack of early stage biomarkers. Genes identified to be aberrantly expressed at the 3q26.2 locus (i.e. SnoN/SkiL) have been implicated in ovarian cancer pathophysiology. We have previously shown that SnoN expression is increased in advanced stage ovarian cancers and alters cellular response to arsenic trioxide (As2O3).<h4>Findings</h4>We now demonstrate increased DNA copy ...[more]

PMID: 23621864

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Project description:BACKGROUND: The GBGT1 gene encodes the globoside alpha-1,3-N-acetylgalactosaminyltransferase 1. This enzyme catalyzes the last step in the multi-step biosynthesis of the Forssman (Fs) antigen, a pentaglycosyl ceramide of the globo series glycosphingolipids. While differential GBGT1 mRNA expression has been observed in a variety of human tissues being highest in placenta and ovary, the expression of GBGT1 and the genes encoding the glycosyltransferases and glycosidases involved in the biosynthesis of Fs as well as the possible involvement of DNA methylation in transcriptional regulation of GBGT1 expression have not yet been investigated. RESULTS: RT-qPCR profiling showed high GBGT1 expression in normal ovary surface epithelial (HOSE) cell lines and low GBGT1 expression in all (e.g. A2780, SKOV3) except one (OVCAR3) investigated ovarian cancer cell lines, a finding that was confirmed by Western blot analysis. Hierarchical cluster analysis showed that GBGT1 was even the most variably expressed gene of Fs biosynthesis-relevant glycogenes and among the investigated cell lines, whereas NAGA which encodes the alpha-N-acetylgalactosaminidase hydrolyzing Fs was not differentially expressed. Bisulfite- and COBRA-analysis of the CpG island methylation status in the GBGT1 promoter region demonstrated high or intermediate levels of GBGT1 DNA methylation in all ovarian cancer cell lines (except for OVCAR3) but marginal levels of DNA methylation in the two HOSE cell lines. The extent of DNA methylation inversely correlated with GBGT1 mRNA and protein expression. Bioinformatic analysis of GBGT1 in The Cancer Genome Atlas ovarian cancer dataset demonstrated that this inverse correlation was also found in primary ovarian cancer tissue samples confirming our cell line-based findings. Restoration of GBGT1 mRNA and protein expression in low GBGT1-expressing A2780 cells was achieved by 5-aza-2'-deoxycytidine treatment and these treated cells exhibited increased helix pomatia agglutinin-staining, reflecting the elevated presence of Fs disaccharide on these cells. CONCLUSIONS: GBGT1 expression is epigenetically silenced through promoter hypermethylation in ovarian cancer. Our findings not only suggest an involvement of DNA methylation in the synthesis of Fs antigen but may also explain earlier studies showing differential GBGT1 expression in various human tissue samples and disease stages.

Dataset Information

Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells.

Publications

Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells.

Similar Datasets

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