Functional Epigenetic Analysis of Prostate Carcinoma: A Role for Seryl-tRNA Synthetase?
Odiljon Ikromov1, Imad Alkamal1, Ahmed Magheli1
1Klinik für Urologie, Charité-Universitätsmedizin Berlin, Charité Campus Mitte (CCM), Charitéplatz 1, 10117 Berlin, Germany.
Abstract:
Transcriptional silencing, as a result of aberrant promoter hypermethylation, is a common mechanism through which genes in cancer cells become inactive. Functional epigenetic screens using demethylating agents to reexpress transcriptional silenced genes may identify such inactivated genes for needing further evaluation. We aimed to identify genes so far not known to be inactivated by promoter hypermethylation in prostate cancer. DU-145 and LNCaP cells were treated with the DNMT inhibitor zebularine. Expression changes of total RNA from treated and untreated cells were compared using an RNA expression microarray. Genes upregulated more than 2-fold were evaluated by RT-qPCR in 50 cases of paired normal and tumor tissues of prostate cancer patients. SARS was found to be downregulated in prostate cancer in 42/50 cases (84%). In addition, GADD45A and SPRY4 showed a remarkable diminished expression (88% and 74%, resp.). The gold standard for promoter hypermethylation-inactivated genes in prostate cancer (GSTP1) was repressed in 90% of our patient samples. ROC analyses reported statistically significant AUC curves in SARS, GADD45A, and GSTP1 and positive Spearman correlations were found between these genes. SARS was discovered to be a novel gene that is repressed in prostate cancer and could therefore be recommended for its involvement in prostate carcinogenesis.
Insights
Aberrant promoter hypermethylation silences genes in cancer. This study identified novel genes, including SARS, repressed in prostate cancer, suggesting their role in carcinogenesis and potential as biomarkers.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Transcriptional silencing via aberrant promoter hypermethylation is a common mechanism for gene inactivation in cancer.
- Functional epigenetic screens can identify genes silenced by hypermethylation.
- Prostate cancer research seeks novel genes inactivated by this mechanism.
Purpose of the Study:
- To identify genes not previously known to be inactivated by promoter hypermethylation in prostate cancer.
- To evaluate the expression changes of potential candidate genes in prostate cancer tissues.
Main Methods:
- Prostate cancer cell lines (DU-145, LNCaP) were treated with the DNMT inhibitor zebularine.
- RNA expression microarrays compared gene expression in treated versus untreated cells.
- Upregulated genes were validated by RT-qPCR in 50 paired normal and tumor prostate cancer tissues.
Main Results:
- SARS was significantly downregulated in 84% of prostate cancer samples.
- GADD45A and SPRY4 showed diminished expression in 88% and 74% of samples, respectively.
- The known hypermethylated gene GSTP1 was repressed in 90% of samples, validating the method.
Conclusions:
- SARS is a novel gene repressed in prostate cancer, potentially involved in carcinogenesis.
- SARS, GADD45A, and GSTP1 show significant downregulation and correlation, suggesting a common regulatory mechanism.
- These findings highlight potential new biomarkers for prostate cancer diagnosis and therapeutic targets.
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