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.