Abstract
Hepatocellular carcinoma (HCC) remains a major health problem worldwide with a continuous increasing prevalence. Despite the introduction of targeted therapies like the multi-kinase inhibitor sorafenib, treatment outcomes are not encouraging. The prognosis of advanced HCC is still dismal, underlying the need for novel effective treatments. Apart from the various risk factors that predispose to the development of HCC, epigenetic factors also play a functional role in tumor genesis. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone lysine residues of proteins, such as the core nucleosome histones, in this way not permitting DNA to loosen from the histone octamer and consequently preventing its transcription. Considering that HDAC activity is reported to be up-regulated in HCC, treatment strategies with HDAC inhibitors (HDACIs) showed some promising results. This review focuses on the use of HDACIs as novel anticancer agents and explains the mechanisms of their therapeutic effects in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, the fifth most frequently diagnosed cancer in men and the eighth most frequently diagnosed cancer in women in the United States [1]
HDAC inhibitors (HDACIs) can be categorized according to their chemical structure into (a) hydroxamates (e.g., suberanilohydroxamic acid (SAHA)), (b) benzamides (e.g., MS275), (c) cyclic peptides and (d) aliphatic acids (e.g., valproic acid (VPA)) [30]
Considering that the expression of Histone deacetylases (HDACs)-1, -2 is up-regulated in HCC, their combined inhibition was proposed by Zhou et al According to their results, there was an increased expression of p21Waf/Cip1 and p19INK4d, which lead to decreased expression of cyclin-dependent kinases (CDKs), cell cycle blockage and apoptosis [44]
Summary
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, the fifth most frequently diagnosed cancer in men and the eighth most frequently diagnosed cancer in women in the United States [1] It is the fourth leading cause of cancer-related death in developed countries [2]. The highest HCC rate is observed among Asians/Pacific Islanders, but Hispanics and African-Americans have shown such an increase in HCC diagnosis that they are predicted to be the groups with the highest HCC rates by 2030 [5,6] These differences are due to variation in the distribution of risk factors and in host genetics or environmental factors [7]. The role of histone deacetylase inhibitors (HDACIs) has been investigated towards this direction [14,15]
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