title: Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells.
abstract: Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation and/or apoptosis in numerous cancer cell types and have shown promise in clinical trials. These agents are particularly novel, given their ability to selectively influence gene expression. Previously, we demonstrated that the HDIs butyrate and trichostatin A (TSA) directly repress c-Src proto-oncogene expression in many cancer cell lines. Activation and/or overexpression of c-Src have been frequently observed in numerous malignancies, especially of the colon. Therefore, our observation was particularly interesting since butyrate is a naturally abundant component of the large intestine and has been suggested to be a cancer-preventive agent. However, c-Src is not the only Src family kinase (SFK) member to be implicated in the development of human cancers, including those of the colon. Therefore, the relative expression levels of known SFKs were examined in a panel of human colon cancer cell lines. We found a surprisingly diverse expression pattern but noted that most cell lines expressed relatively high levels of at least 2 SFKs. When the effects of butyrate and TSA were examined in representative cell lines, the expression of all SFKs was repressed in a dose- and time-dependent manner. Further, detailed examination of Lck, Yes and Lyn demonstrated that this repression had a direct effect on transcription and was independent of new protein synthesis. These results mirror our earlier data obtained with c-Src and suggest that SFKs are a major target of HDIs and likely account in part for the anticancer effects of these promising new drugs.
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Calley L
authors.initials: CL
authors.lastname: Hirsch
authors.forename: Erin L
authors.initials: EL
authors.lastname: Smith-Windsor
authors.forename: Keith
authors.initials: K
authors.lastname: Bonham
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D015500:Chloramphenicol O-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051575:Proto-Oncogene Proteins c-yes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C012589:trichostatin A; D015500:Chloramphenicol O-Acetyltransferase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D015688:Oncogene Protein pp60(v-src); D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases