Induction of TAp63 by histone deacetylase inhibitors

Abstract

TAp63 belongs to the p53-tumour suppressor family and is capable of transactivating a set of target genes to induce cell cycle arrest and apoptosis. We showed that treatment of cancer cells with chemo-therapeutic drugs or the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) results in induction of TAp63 expression, which is in turn related with chemosensitivity. Indeed, induction of TAp63 by TSA affects sensitivity to chemo-therapeutic drugs via the cleavage of the trans-inhibitory domain of TAp63 by active caspases, resulting in generation of a transcriptionally hyper-active TAp63 fragment. Therefore therapeutic approaches that enhance TAp63 expression may offer an improvement in the management of chemoresistant tumours. In this study we tested the abilities of different HDAC inhibitors to induce TAp63 expression. We discovered that two HDAC inhibitors belonging to the hydroxamate group, namely TSA and LBH589, are the most efficient inducers of TAp63 expression. Finally, we found that induction of TAp63 expression in HCT116 cells depends on p53, as p53-negative HCT116 cells failed to induce significant TAp63 expression following treatment with different HDAC inhibitors.