Regulation of apoptosis-associated genes by histone deacetylase inhibitors: implications in cancer therapy

Anomalous gene regulation, dictated by epigenetic modifications, is a universal characteristic of cancer cells. Histone deacetylases (HDACs) are an important class of enzymes that influence gene expression by the removal of acetyl groups from histones leading to chromatin remodeling and transcriptional suppression of key apoptosis and cell cycle regulatory genes. Histone deacetylase inhibitors (HDACis) are a novel category of anticancer pharmacological agents developed to counter the actions of HDACs, thus, inducing an array of cellular consequences, such as apoptosis, cell cycle arrest, generation of reactive oxygen species, inhibition of angiogenesis, and autophagy. Suberoylanilide hydroxamic acid (SAHA, Zolinza, Vorinostat), is currently the only Food and Drug Administration-approved HDACi for the treatment of cutaneous T-cell lymphoma. SAHA and other HDACis have shown selective toxicity toward malignant cells while sparing the surrounding normal cells. In addition to this specificity, their regulation of apoptosis-associated genes and the synergistic augmentation of apoptotic events when used simultaneously with other anticancer agents such as conventional chemotherapies, radiation, inhibitors of DNA methylation, and proteasome inhibitors make HDACis potential novel arsenals in the battle against cancer. Herein I review epigenetic modifications, discuss the various mechanisms of HDACi-induced effects, in particular modulation of expression of apoptosis-associated gene products, and highlight SAHA and its antitumor functions.