Invasion of v-Fos(FBR)-transformed cells is dependent upon histone deacetylase activity and suppression of histone deacetylase regulated genes.
Transformation of fibroblasts with the v-fos oncogene produces a highly invasive phenotype that is mediated by changes in gene expression. Inhibition of histone deacetylase (HDAC) activity with trichostatin A (TSA) or valproic acid (VPA) at concentrations that do not affect morphology, motility, chemotaxis or proliferation, strongly inhibits invasion and results in the re-expression of a significant proportion of those genes that are downregulated in the v-Fos-transformed cells. Independent expression of three of these re-expressed genes, (Ring1 and YY1 binding protein (RYBP); protocadherin gamma subfamily C,3 (PCDHGC3); and signal transducer and activator of transcription 6 (STAT6)) in Fos-transformed cells, has no effect on morphology, motility, chemotaxis or proliferation, but strongly inhibits invasion. Therefore, we conclude that the ability of v-Fos-transformed cells to invade is dependent upon repression of gene expression through either direct or indirect HDAC activity.
McGarry
Lynn C
LC
Beatson Laboratories, Beatson Institute for Cancer Research, Cancer Research UK, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Winnie
Joseph N
JN
Ozanne
Bradford W
BW
D000199:Actins / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D002633:Chemotaxis; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D018613:Microscopy, Confocal; D008858:Microscopy, Phase-Contrast; D009361:Neoplasm Invasiveness; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology
D000199:Actins; D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins; D006877:Hydroxamic Acids; D016761:Oncogene Proteins v-fos; D012097:Repressor Proteins; C120616:Rybp protein, mouse; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; C012589:trichostatin A; D014635:Valproic Acid; D012313:RNA; D006655:Histone Deacetylases