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.

Invasion of normal human fibroblasts induced by v-Fos is independent of proliferation, immortalization, and the tumor suppressors p16INK4a and p53.

Invasion is generally perceived to be a late event during the progression of human cancer, but to date there are no consistent reports of alterations specifically associated with malignant conversion. We provide evidence that the v-Fos oncogene induces changes in gene expression that render noninvasive normal human diploid fibroblasts highly invasive, without inducing changes in growth factor requirements or anchorage dependence for proliferation. Furthermore, v-Fos-stimulated invasion is independent of the pRb/p16(INK4a) and p53 tumor suppressor pathways and telomerase. We have performed microarray analysis using Affymetrix GeneChips, and the gene expression profile of v-Fos transformed cells supports its role in the regulation of invasion, independent from proliferation. We also demonstrate that invasion, but not proliferation, is dependent on the activity of the up-regulated epidermal growth factor receptor. Taken together, these results indicate that AP-1-directed invasion could precede deregulated proliferation during tumorigenesis and that sustained activation of AP-1 could be the epigenetic event required for conversion of a benign tumor into a malignant one, thereby explaining why many malignant human tumors present without an obvious premalignant hyperproliferative dysplastic lesion.