Liver cancer is the sixth most prevalent malignancy worldwide. Due to limited effective treatment options it is the third highest cause of cancer related mortality. Although the molecular mechanisms underlying liver cancer are poorly understood, mounting evidence implicates liver progenitor cells (LPCs) as a potential source of liver cancers. The CDKN2A gene, which encodes the ARF and INK4A tumour suppressors, has been identified as one of the most frequently mutated genes in liver cancer. Our studies indicate that the deletion of the CDKN2A gene accompanies LPC tumorigenic transformation. To determine whether the loss of the CDKN2A gene directly contributes to LPC transformation, we derived LPC lines from Arf-/- mouse embryos. Although the Ink4a gene remained intact in the Arf-/- LPC lines, they did not express INK4A although its expression could be restored upon treatment with 5-azacytidine. Arf-/- LPC lines transformed during continuous culture, suggesting that deletionof Arf may predispose LPCs to transformation. Transformed Arf-/- LPCs displayed increased Slug and Vimentin expression and decreased expression of epithelial markers EpCAM and E-cadherin indicative of an epithelial to mesenchymal transition. Interestingly, treatment of the transformed cells with HDAC inhibitors (sodium butyrate or trichostatin A) restored an epithelial phenotype and the cells adopted a differentiated morphology suggesting a mesenchymal to epithelial transition had occurred. Furthermore, treatment led to fewer and smaller colonies when transformed Arf-/- LPCs were assayed in soft agar. Similar results were also observed in other transformed LPC lines derived from p53-/- mice suggesting that epigenetic changes in addition to the loss of key tumour suppressor genes contribute to LPC transformation.