The resetting of Epigenetics is a common feature of cancer cells. By contrast how epigenetic regulators can trigger the oncogenic transformation is mystery. Previous studies reported that the hyper-activation of the epigenetic regulator HDAC4 transforms murine cells. However, the transformation process is more complex in human cells that are relatively resistant to oncogenesis. In the present thesis we addressed the oncogenic potential of HDAC4 in human primary fibroblasts (BJ). The over-expression of an hyper-active mutant of HDAC4 in human fibroblast triggers a permanent cell cycle arrest typical of premature senescent cells after the exposure to strong oncogenes. The contemporary inactivation of p53 and pRb/p16 pathways achieved by the transduction of the cells with SV40 LT allows the transformation of HDAC4-TM cells. Transcriptomic analysis of HDAC4-TM and RAS transformed cells evidenced that both the oncogenes require the repression of the interferon-response to transform the human cells. Further we have compared our signature with other two oncogenes like RAS and c-MYC which favour in vitro transformation in BJ-hTERT SV40 LT/ST. The tumorigenic properties driven by the three oncogenes rely on the activation of some common molecular pathways, but not on the activation and repression of the same genes. Importantly, commonly dysregulated genes, both up-regulated and down-regulated during in vitro transformation contribute to a worst survival rate in some cancer types. To gain insight on the cellular pathways supervised by HDAC4 and responsible for the transformation of human cells we investigated the genomic instability of leiomyosarcoma cells knocked out of HDAC4. In this cancer cell removal of HDAC4 results in the induction of cellular senescence through the augmentation of the DNA damage and the activation of the interferon response.
