Profiling of selenomethionine responsive genes in colon cancer by microarray analysis.
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.
Goulet
Anne-Christine
AC
Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
Watts
George
G
Lord
Jean L
JL
Nelson
Mark A
MA
D045744:Cell Line, Tumor; D002843:Chromatin / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics*; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D006657:Histones / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012645:Selenomethionine / Q000494:pharmacology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D002843:Chromatin; D000072259:Connexin 26; D017630:Connexins; D006657:Histones; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D012645:Selenomethionine; D000099184:Serum-Glucocorticoid Regulated Kinases; C000607042:GJB2 protein, human