Histone Deacetylases and Histone Deacetylase Inhibitors: Molecular Mechanisms of Action in Various Cancers

Abstract

Epigenetic modifications such as histone modification play an important role in tumorigenesis. There are several evidence that histone deacetylases (HDACs) play a key role in cancer induction and progression by histone deacetylation. Besides, histone acetylation is being accessed as a therapeutic target because of its role in regulating gene expression. HDAC inhibitors (HDACIs) are a family of synthetic and natural compounds that differ in their target specificities and activities. They affect markedly cancer cells, inducing cell differentiation, cell cycle arrest and cell death, reduction of angiogenesis, and modulation of the immune system. Here, we summarize the mechanisms of HDACs and the HDACIs in several cancers. An online search of different sources such as PubMed, ISI, and Scopus was performed to find available data on mechanisms and pathways of HDACs and HDACIs in different cancers. The result indicated that HDACs induce cancer through multiple mechanisms in various tissues. This effect can be inhibited by HDACIs which affect cancer cell by different pathways such as cell differentiation, cell cycle arrest, and cell death. In conclusion, these findings indicate that the HDACs play a major role in carcinogenesis through various pathways, and HDACIs can inhibit HDAC activity by multiple mechanisms resulting in cell cycle arrest, cell growth inhibition, and apoptosis induction.

Keywords: Cancer; histone deacetylase; histone deacetylase inhibitors.

Figure 1

Acetylation and deacetylation reactions of lysine catalyzed by histone acetyltransferases and histone deacetylases

Figure 2

Histone acetylation at the N-terminus lysine by histone acetyltransferases and histone deacetylation by histone deacetylases

Figure 3

Histone acetylation converts chromatin to an open state, it is regulated by the histone acetyltransferase (HAC). Histone deacetylation is regulated by the histone deacetylase which converts chromatin structure to a condensed or transcriptionally repressive state

Figure 4

Classification, structures, and cellular localization of Zn²⁺-dependent histone deacetylase isoforms

Figure 5

Multiple antitumor pathways activated by histone deacetylase inhibitors. Extrinsic and intrinsic refer to two apoptosis pathways, and homologous recombination and nonhomologous end joining refer to two double strand breaks (DBS) repair pathways

Figure 6

Chemical structure of several histone deacetylase inhibitors

Figure 7

The mechanism of histone deacetylase inhibitorsHDACIs against ovarian cancer

Figure 8

Characterized mechanisms of histone deacetylasesHDACs in pancreatic ductal adenocarcinomaPDAC. Three histone deacetylasesHDAC pathways are demonstrated. Right part: histone deacetylasesHDACs control expression of the CDKI p21Cip1/Waf1 and cyclin B1 to control the G1/S-phase or G2/M-phase or the cell cycle. Middle part: histone deacetylasesHDACs contribute to the imbalanced expression of the anti-apoptotic (BCLw, MCL1, BCLXL, and c-Flip) and pro-apoptotic (BIM, BAX, and NOXA) genes. Left part: histone deacetylases HDAC1 and 2 containing repressor complex is recruited to the E-box of the E-cadherin promoter by the transcription factor SNAIL