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.
Medical Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea. kschung@kribb.re.kr
Kyung-Sook
KS
Chung
Jiwon
J
Ahn
Chung-Hae
CH
Choi
Nam Hui
NH
Yim
Chang-Mo
CM
Kang
Chun-Ho
CH
Kim
Kyeong
K
Lee
Hee-Moon
HM
Park
Kyung-Bin
KB
Song
Misun
M
Won
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