Histone deacetylase inhibitors: molecular mechanisms of action

Xu, Weisheng; Parmigiani, Raphael B.; Marks, Paul A.

doi:10.1038/sj.onc.1210620

Cited by 1,329 publications

(1,314 citation statements)

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“…It is conceivable that these modification signatures have combinatorial roles in regulating the biological activity of proteins (Sims and Reinberg, 2008). Drug-induced alterations of nonhistone protein modification signatures could therefore have a major role in the pharmacological responses to HDAC inhibitors (Xu et al, 2007).…”

Section: Are Hdac Inhibitors Epigenetic Drugs?mentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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Section: Are Hdac Inhibitors Epigenetic Drugs?mentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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“…A number of HDAC inhibitors are in clinical development as anticancer agents (Xu et al, 2007), and one of them, suberoylanilide hydroxamic acid, has recently been approved for the treatment of advanced cutaneous T cell lymphoma (Marks, 2007). While most of the HDACs are localized in the nucleus, HDAC6 is a cytoplasmic protein associated with the cytoskeleton and involved in cytoskeleton-related activities (Boyault et al, 2007;Valenzuela-Fernández et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.

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“…Inhibitors of DNA methylation (cytosine analogs; 5-azacytidine and 5-aza-2 0 -deoxycytidine) are currently used for the treatment of myelodysplastic syndrome and the first two HDAC inhibitors, vorinostat and romidepsin, have been approved by the FDA for the treatment of cutaneous T-cell lymphoma (http://clinicaltrials.gov) (Drummond et al, 2005;Grant et al, 2007;Xu et al, 2007). With the identification of large families of histone methyltransferases and demethylases The use of epi-drugs for therapy has both advantages and drawbacks.…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Histone deacetylase inhibitors: molecular mechanisms of action

Cited by 1,329 publications

References 109 publications

Epigenetic cancer therapy: rationales, targets and drugs

Epigenetic cancer therapy: rationales, targets and drugs

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Towards novel paradigms for cancer therapy

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