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Published on: September 25, 2011
Profiling of selenomethionine responsive genes in colon cancer by microarray analysis
Anne-Christine Goulet1, George Watts, Jean L Lord
1Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
Abstract:
High-selenium containing yeast is being evaluated in clinical trials against colon polyp recurrence. However, the molecular targets for the anticancer effects of selenium remain unclear. Previous studies by our group demonstrated that selenomethionine-induced growth arrest appears to be mediated by activation of ERK and subsequent phosphorylation of RSK and histone H3. These results suggest that selenomethionine can alter gene expression. In the present study, we have used cDNA microarrays to determine whether gene expression differences exist in HCT116 colon cancer cells treated with selenomethionine. These experiments reveal statistically significant expression changes for 50 genes. Genes we found to increase with selenomethionine treatment include KLK6, ATOX1, SGK, GJB2, DAP-1, PLAU, VIM, DPYSL2, STC2 and PXN. Conversely, genes downregulated by selenomethionine include PRKACB, LIM, DEPP, MYC, CDH5, ELF3, VSNL1, SAT and EGLN3. Further analysis of those genes using chromatin immunoprecipitation experiments showed that phosphorylated histone H3 on serine 10 bound to the GJB2 promoter (connexin 26) or the serum glucocorticoid kinase promoter is increased with selenomethionine treatment. Cells overexpressing CX26 or DAP-1 displayed a reduced number of colonies which suggests that these two genes could play a functional role in the growth inhibitory effects of selenomethionine. These data support the notion that selenomethionine-induced growth inhibition is associated with global changes in gene expression. They also demonstrate that selenomethionine can modify chromatin state to alter gene transcription. Finally, our studies provide a practical foundation for the further development of biomarkers to monitor the efficacy of selenomethionine in clinical trials.
Insights
Selenium, specifically selenomethionine, shows promise in preventing colon polyp recurrence by altering gene expression and modifying chromatin. This research identifies key genes and supports selenium
Area of Science:
- Molecular Biology
- Cancer Research
- Nutritional Biochemistry
Background:
- Selenium's anticancer effects are under investigation for colon polyp recurrence.
- Previous work linked selenomethionine-induced growth arrest to ERK/RSK/histone H3 pathway activation.
- The precise molecular targets of selenium's anti-cancer properties require further elucidation.
Purpose of the Study:
- To investigate global gene expression changes in HCT116 colon cancer cells treated with selenomethionine.
- To identify specific genes modulated by selenomethionine that may contribute to its anti-cancer effects.
- To explore the role of chromatin modification in selenomethionine-mediated gene transcription.
Main Methods:
- Utilized cDNA microarrays to analyze gene expression profiles in response to selenomethionine.
- Performed chromatin immunoprecipitation experiments to assess histone modifications at specific gene promoters.
- Conducted functional assays with cells overexpressing candidate genes (CX26, DAP-1) to evaluate colony formation.
Main Results:
- Identified 50 genes with statistically significant expression changes, including upregulated (KLK6, GJB2) and downregulated (MYC, CDH5) genes.
- Demonstrated increased binding of phosphorylated histone H3 to the GJB2 (connexin 26) and SGK promoters upon selenomethionine treatment.
- Overexpression of CX26 and DAP-1 resulted in a reduced number of colonies, suggesting their involvement in growth inhibition.
Conclusions:
- Selenomethionine-induced growth inhibition in colon cancer cells is associated with global alterations in gene expression.
- Selenomethionine can modify chromatin state, leading to changes in gene transcription.
- The identified genes (CX26, DAP-1) and pathways provide a foundation for developing biomarkers to monitor selenomethionine efficacy in clinical settings.
