Trichostatin A inhibits both ras-induced neurite outgrowth of PC12 cells and morphological transformation of NIH3T3 cells.
During screening for inhibitors of ras-mediated differentiation of PC12 cells, trichostatin A (TSA) was isolated from the metabolites of Streptomyces as a potent inhibitor. TSA blocked both oncogenic ras- and NGF-induced neurite outgrowth from PC12 cells. However, addition of TSA 1 h after NGF-stimulation did not inhibit neuronal differentiation, suggesting that TSA affects an early step in the NGF-signaling pathway mediated by ras. Northern blotting analysis showed that TSA prolonged the maximum expression period of c=fos mRNA triggered by NGF and delayed its return to the basal level. TSA reduced c-jun mRNA induction by NGF but greatly enhanced c-myc mRNA induced by NGF. Yoshida et al. (J. Biol. Chem, 265, 17174-17179, 1990) showed that TSA inhibits histone deacetylation, which might influence the gene expression involved in cellular differentiation. In this study, we also found that TSA prevents histone deacetylation in PC12 cells as well as other cell lines, suggesting that inhibition of histone deacetylation by TSA might affect the expression of early-response genes. We also demonstrated that TSA induced reversion of oncogenic ras-transformed NIH3T3 cells to a normal morphology, suggesting that inhibitors of ras-mediated differentiation of PC12 cells may be effective as anticancer agents.
Futamura
M
M
Oncogene Research Laboratory, Banyu Tsukuba Research Institute (Merck), Japan.
Monden
Y
Y
Okabe
T
T
Fujita-Yoshigaki
J
J
Yokoyama
S
S
Nishimura
S
S
D016475:3T3 Cells; D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D013997:Time Factors
D006657:Histones; D006877:Hydroxamic Acids; D009414:Nerve Growth Factors; C012589:trichostatin A