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p53 at the Crossroads Between Different Types of HDAC Inhibitor-Mediated Cancer Cell Death


p53 at the Crossroads Between Different Types of HDAC Inhibitor-Mediated Cancer Cell Death

Maria Mrakovcic et al. Int J Mol Sci.


Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, 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 deacetylase-mediated acetylation of both 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, which are either mutually exclusive or activated in combination. Here, we compile known molecular signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that determine the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to determine the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment.

Keywords: HDAC; HDACi; SAHA; apoptosis; autophagy; cancer; cell death; p53; tumor.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Known mechanisms of histone deacetylase inhibitor-induced (HDACi) re-activation of apoptosis. These activate the intrinsic (mitochondrial) the extrinsic (death-receptor) or both pathways of apoptosis. Also non-coding RNAs, of which microRNAs prevail, have been described to mediate HDACi-stimulated apoptosis.
Figure 2
Figure 2
Known mechanisms and signaling pathways involved in histone deacetylase inhibitor-activated induction or suppression of autophagy. In most cases mTOR inhibition representing the canonical pathway, ROS accumulation, NF-κB hyperacetylation, p21 upregulation, or the involvement of p53 signaling is observed.

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