The International Journal of Biochemistry & Cell Biology
Molecules in focusMolecular basis of the anti-cancer effects of histone deacetylase inhibitors
Section snippets
HDACs and protein acetylation
Epigenetics is defined as the reversible heritable changes in gene activity that occur without a change in the sequence of nuclear DNA. Chromatin consists of DNA wrapped around histone proteins, organized in structural units termed nucleosomes (Richmond and Davey, 2003). Hence, the term epigenetics often, but not exclusively, refers to modifications of the histone proteins. The architecture and compaction of chromatin is modified by covalent posttranslational modifications of the histones.
HDAC inhibitors
HDAC inhibitors (HDACIs) are a diverse group of compounds that induce, to a variable extent, growth arrest, differentiation or apoptosis in vitro and growth arrest of tumors in mouse models. Treatment of cancer cells with HDACI induces histone hyperacetylation and changes in a variety of proteins associated with proliferation and apoptosis (Johnstone, 2002, Minucci and Pelicci, 2006).
Molecules of a relatively wide range of chemical structures are able to inhibit the activities of HDACs (Minucci
HDACI and cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCLs) encompass a heterogeneous group of rare extranodal lymphoproliferative disorders (Kim et al., 2005, Siegel et al., 2000). Primary CTCLs are characterized by the localization of the clonally derived, malignant lymphocytes to the skin at presentation (Siegel et al., 2000). The most common form of CTCL, mycosis fungoides (MF), is indolent but may transform to large cell lymphoma or evolve into a leukemic variant, Sézary syndrome (SS) (Kim et al., 2005). The
HDACI: mechanisms of action
Which signaling pathways are particularly affected by pharmacological serum concentrations of HDACI? Answer to these question may assist in the development of combination therapies to enhance treatment outcomes by optimizing the regulation, shutdown or activation of the targeted pathway. As for HDACI, we do not know the key target(s) for HDACI action, because many non-histone protein substrates could be instrumental in mediating the anti-cancer effects of HDACIs. Alternatively, the simultaneous
Acknowledgements
Grant support: Centre for Biomedical Genetics, Cancer Genomics Centre and the Dutch Cancer Society (KWF).
We apologize to the authors whose research articles could not be cited due to space constraints.
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Cited by (16)
Adverse effect of valproic acid on an in vitro gastrulation model entails activation of retinoic acid signaling
2016, Reproductive ToxicologyCitation Excerpt :Consistently, in mouse embryonic stem cells, HDAC1/2/3 bind to the RARE-containing enhancer sequence of the Hoxa1 gene and knockdown of any one of HDAC1/2/3 is sufficient to up-regulate Hoxa1 transcription [98]. Interestingly, treatment with HDAC inhibitors potentiates responses of various cancer cells to RA, including myeloid leukemia, prostate carcinoma, neuroblastoma, and embryonal carcinoma [99–104]. Because activation of RA signaling causes cell cycle arrest, apoptosis, and differentiation in many cancer cells, HDAC inhibitors have been explored as effective chemotherapy agents [105].
Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer
2014, Cancer LettersCitation Excerpt :HDACs acetyl moiety from lysine residues of histone tail, leading to compaction of chromatin structure and transcriptional repression. Conversely, histone acetyltransferases (HATs) involve in the addition of acetyl group to histone, resulting in relaxed chromatin configuration and activation of transcription [18,19]. A disrupted balance between acetylation and deacetylation results in aberrant expression of a wide range of genes affecting the regulation of proliferation, apoptosis, metastasis and angiogenesis [20].
Smoke exposure of human macrophages reduces HDAC3 activity, resulting in enhanced inflammatory cytokine production
2012, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :Nevertheless, there are a number of caveats to using transformed cell lines for these studies. Firstly, the regulation of chromatin condensation by HAT and HDACs is clearly dysregulated in tumor cell lines; indeed, HDAC inhibitors are effective inducers of apoptosis in many tumor lines and have also been studied as clinical cancer therapeutics [38–43]. It is also clear that AM are a distinct population of monocyte-derived MØ.
γ-H2AX and other histone post-translational modifications in the clinic
2012, Biochimica et Biophysica Acta - Gene Regulatory MechanismsCitation Excerpt :One example of the growing use of compounds for modifying chromatin is that of histone deacetylase inhibitors (HDACis) (Tables 1, 4). Treatment of cancer cells with HDACis induces histone hyperacetylation and changes in the levels of a large range of proteins associated with apoptosis and proliferation (see [114] for review). In the first study reporting a clinical response to an HDACi, romidepsin (also referred to depsipeptide) was administered to patients with T-cell lymphoma.
Efficacy of novel histone deacetylase inhibitor, AR42, in a mouse model of, human T-lymphotropic virus type 1 adult T cell lymphoma
2011, Leukemia ResearchCitation Excerpt :In contrast, the inhibitors of HDACs (HDACi) promote the acetylated state of histone proteins and relaxed chromatin structure. The role of HDACi in cancer therapy has been reviewed [7,8]. The HDACi are divided into several classes including short chain fatty acids, hydroxamic acids, benzamides, and cyclic peptides.