Regulation of HDACi−Triggered Autophagy by the Tumor Suppressor Protein p53

Cancer is a complex genetic and epigenetic-based disease that has developed a multitude of mechanisms in evading cell death. Deregulation of apoptosis and autophagy are commonly encountered during the development of human tumors. Histone deacetylase inhibitors (HDACi) have been employed to reverse epigeneti-cally deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear however. Experimental evidence of the last decade convincingly reports that the frequently mutated tumor suppressor protein p53 can act either as an activator or as an inhibitor of autophagy depending on its subcellular localization, and linked to its mode of action. Consistently, we recently described p53 as a regulatory switch that governs if histone deacetylase inhibitor-adminis-tered uterine sarcoma cells undergo autophagy or apoptosis. By highlighting this novel finding, we summarize in this chapter the role of p53-mediated signaling during the activation of the autophagic pathway in tumor cells in response to HDACi.