Chemical genetic modifier screens: small molecule trichostatin suppressors as probes of intracellular histone and tubulin acetylation.
Histone deacetylase (HDAC) inhibitors are being developed as new clinical agents in cancer therapy, in part because they interrupt cell cycle progression in transformed cell lines. To examine cell cycle arrest induced by HDAC inhibitor trichostatin A (TSA), a cytoblot cell-based screen was used to identify small molecule suppressors of this process. TSA suppressors (ITSAs) counteract TSA-induced cell cycle arrest, histone acetylation, and transcriptional activation. Hydroxamic acid-based HDAC inhibitors like TSA and suberoylanilide hydroxamic acid (SAHA) promote acetylation of cytoplasmic alpha-tubulin as well as histones, a modification also suppressed by ITSAs. Although tubulin acetylation appears irrelevant to cell cycle progression and transcription, it may play a role in other cellular processes. Small molecule suppressors such as the ITSAs, available from chemical genetic suppressor screens, may prove to be valuable probes of many biological processes.
Koeller
Kathryn M
KM
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Haggarty
Stephen J
SJ
Perkins
Brian D
BD
Leykin
Igor
I
Wong
Jason C
JC
Kao
Ming-Chih J
MC
Schreiber
Stuart L
SL
D000107:Acetylation; D002453:Cell Cycle / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005821:Genetic Techniques; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015394:Molecular Structure; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014404:Tubulin; C012589:trichostatin A