Abstract
Tumor development and progression is the consequence of genetic as well as epigenetic alterations of the cell. As part of the epigenetic regulatory system, histone acetyltransferases (HATs) and deacetylases (HDACs) drive the modification of histone as well as non-histone proteins. Derailed acetylation-mediated gene expression in cancer due to a delicate imbalance in HDAC expression can be reversed by histone deacetylase inhibitors (HDACi). Histone deacetylase inhibitors have far-reaching anticancer activities that include the induction of cell cycle arrest, the inhibition of angiogenesis, immunomodulatory responses, the inhibition of stress responses, increased generation of oxidative stress, activation of apoptosis, autophagy eliciting cell death, and even the regulation of non-coding RNA expression in malignant tumor cells. However, it remains an ongoing issue how tumor cells determine to respond to HDACi treatment by preferentially undergoing apoptosis or autophagy. In this review, we summarize HDACi-mediated mechanisms of action, particularly with respect to the induction of cell death. There is a keen interest in assessing suitable molecular factors allowing a prognosis of HDACi-mediated treatment. Addressing the results of our recent study, we highlight the role of p53 as a molecular switch driving HDACi-mediated cellular responses towards one of both types of cell death. These findings underline the importance to determine the mutational status of p53 for an effective outcome in HDACi-mediated tumor therapy.
Highlights
histone deacetylases (HDACs) Inhibitors as Epigenetic Cancer DrugsCancer is an intensively investigated versatile complex disease resulting from genetic alterations that provoke constitutive activation of oncogenes or functional silencing of tumor suppressor genes [1,2,3]
We summarize histone deacetylase inhibitors (HDACi)-mediated mechanisms of action, with respect to the induction of cell death
Future experiments need to explore the exact underlying molecular mechanisms that were found in the direct interference of SAHA with HDAC activity responsible for deacetylating the non-histone protein p53
Summary
Cancer is an intensively investigated versatile complex disease resulting from genetic alterations that provoke constitutive activation of oncogenes or functional silencing of tumor suppressor genes [1,2,3]. A deeper knowledge of the mechanisms of action and identification of predictors related to cell death and resistance could pave the way for a more targeted use of HDACi in cancer therapy This strategy would include the ability to determine who will benefit from a specific HDACi treatment by distinct biomarkers [17]. Recent experimental evidence of our group imply that contingent on the presence or absence of p53 protein in tumor cells [18], HDACi administration could either elicit an apoptotic or autophagic cellular response, respectively These findings should be integrated into the deliberation of HDACi treatment in clinical trials and help to optimize future therapeutic decisions related to cancer treatment. We discuss the cell death mechanisms elicited by HDACi in cancer treatment, with a special focus on the role of p53 and its involvement in cell death mechanisms
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