The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin.
Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-up-regulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Lisa M
LM
Butler
Xianbo
X
Zhou
Wei-Sheng
WS
Xu
Howard I
HI
Scher
Richard A
RA
Rifkind
Paul A
PA
Marks
Victoria M
VM
Richon
D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects*; D003001:Cloning, Molecular; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D013879:Thioredoxins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
D002352:Carrier Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C486715:TXNIP protein, human; D013879:Thioredoxins; D000077337:Vorinostat