Mediation of transformation by the v-fos oncogene: regulation of the invasive phenotype by histone deacetylases

McGarry, Lynn C (2004). Mediation of transformation by the v-fos oncogene: regulation of the invasive phenotype by histone deacetylases. PhD thesis The Open University.



Transformation of fibroblasts with the v-fos oncogene produces a highly invasive phenotype. Accordingly, genes up- and down-regulated by v-Fos are of crucial importance in mediating a multigenic invasion programme. Differential expression studies revealed that components of histone deacetylase (HDAC) transcriptional co-repressor complexes are up-regulated in FBR-v-Fos-transformed (FBR) cells. Since HDACs facilitate gene silencing, we investigated the consequences of inhibiting their activity in terms of gene re-expression and phenotypic changes. We treated FBR cells with the HDAC inhibitors, trichostatin A (TSA) and valproic acid (VPA), at a range of sub-growth-inhibitory concentrations. At higher concentrations within this range, actin stress-fibres reform, transformed morphology reverts, cells are less motile and invasion is inhibited. Significantly, however, at lower concentrations within this range we inhibit invasion and actin stress-fibres reform but morphology, motility and chemotaxis are unaffected. This demonstrates the involvement of different groups of genes in different aspects of the transformed phenotype. In a limited study, we found several genes, down-regulated in FBR cells, which are then re-expressed as a consequence of HDAC inhibition. Ectopic re-expression (stable and transient) of three of these genes (RYBP, PCDHGC3 and STAT6) individually, in FBR cells, inhibits invasion without affecting morphology, motility or chemotaxis; nor do actin stress-fibres reform. These results demonstrate that the down-regulation of genes by Fos can be mediated by histone deacetylases and that many of these down-regulated genes, when normally expressed in fibroblasts, function to maintain the non-invasive state, in that their expression is incompatible with the invasive phenotype.

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