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

Abstract

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 epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase-and deacetylasemediated 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-administered 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.

Molecular Determinants of Cancer Therapy Resistance to HDAC Inhibitor-Induced Autophagy

“…Treatment with HDACi has exposed several varying molecular signaling mechanisms leading to the activation or suppression of HDACi-mediated autophagy (reviewed previously in [121][122][123][124][125][126][127] Figure 2 and Table 1). In by far most cases, mTOR inhibition involving the canonical pathway, followed by ROS accumulation, NF-κB hyperacetylation, p21 upregulation, or the involvement of p53 signaling, is observed during autophagic activation [49,58,[128][129][130][131][132][133][134][135][136][137][138][139][140][141][142].…”

Epigenetic Immunomodulatory effect of Eugenol and Astaxanthin on Doxorubicin Cytotoxicity in Hormonal Positive Breast Cancer Cells

“…This histone deacetylase inhibition activity observed with EUG illustrates its proautophagic effect and intrinsic apoptotic cell death. On the same way, most of histone deacetylase inhibitors can induce mitochondria-mediated apoptosis and provoke autophagy-induced caspase-independent cell death [75,76]. The inhibitory effect of AST on histone deacetylase 9 expressions was observed [77].…”

Epigenetic Immunomodulatory Effect of Eugenol and Astaxanthin on Doxorubicin Cytotoxicity in Hormonal Positive Breast Cancer Cells

“…This histone deacetylase inhibition activity observed with EUG illustrates its proautophagic effect and intrinsic apoptotic cell death. On the same way, most of histone deacetylase inhibitors can induce mitochondria-mediated apoptosis and provoke autophagy-induced caspase-independent cell death [69,70]. The inhibitory effect of AST on histone deacetylase 9 expressions was observed [71].…”