Targeting Histone Deacetylases in Diseases: Where Are We?

Abstract

Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death.

Recent advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy.

Critical issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes.

Future directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment.

FIG. 1.

HDAC and SIRT classification. Enzymes are divided into classes and sub-classes; subcellular localization and tissue distribution are reported for each member. HDAC, histone deacetylase; SIRT, sirtuin. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Structures of major HDACi belonging to classes of hydroxamic acids, benzamides, aliphatic acids, and cyclic tetrapeptides/depsipeptides. HDACi, histone deacetylase inhibitors.

FIG. 3.

HDACs control many aspects of cancer biology. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

World map showing distribution of Vorinostat currently in clinical trials. Colors indicate the number of studies with locations in that region. Some trials are carried out simultaneously in different countries. Downloaded and modified from clinicaltrials.gov. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Clinical trials with Mocetinostat (MGCD0103). Studies are divided according to phase progression. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Clinical trials with Entinostat (MS-275) by topic classification. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Mechanisms leading to cell death and possible interfering causes in response to HDACi treatment in cancer cells. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Schematic representation of the unbalanced number of trials with HDACi as a single drug and in combination regimens.