Fission yeast-based screening to identify putative HDAC inhibitors using a telomeric reporter strain.
Transcriptional silencing is regulated by promoter methylation and histone modifications such as methylation and acetylation. We constructed a Schizosaccaromyces pombe reporter strain, KCT120a, to identify modifiers of transcriptional silencing, by inserting the ura4(+) gene into a heterochromatic telomere region. Two compounds inhibited the activity of histone deacetylases, induced acetylation of histone H3 and caused apoptotic cell death in HeLa cells. Expression of gelsolin and p21(waf1/cip1) also increased, as it does in response to HDAC inhibitors such as TSA. Therefore, these compounds appear to be potent inhibitors of HDACs, and hence potential anti-cancer drugs. Our observations suggest that a yeast cell-based assay system for transcriptional silencing may be useful for identifying histone deacetylase inhibitors and other agents affecting chromatin remodeling.
Chung
Kyung-Sook
KS
Medical Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea. kschung@kribb.re.kr
Ahn
Jiwon
J
Choi
Chung-Hae
CH
Yim
Nam Hui
NH
Kang
Chang-Mo
CM
Kim
Chun-Ho
CH
Lee
Kyeong
K
Park
Hee-Moon
HM
Song
Kyung-Bin
KB
Won
Misun
M
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D018260:Gelsolin / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D018260:Gelsolin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A