Inhibition of Histone Deacetylases: A Pharmacological Approach to the Treatment of Non-Cancer Disorders

Wiech, N. L.; Fisher, Jed F.; Helquist, Paul; Wiest, Olaf

doi:10.2174/156802609788085241

Cited by 66 publications

(60 citation statements)

References 104 publications

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“…We note that inhibitors of lysine deacetylases, mimicking HATs, are used to induce pluripotent stem cells (48) and are widely emerging as important drug targets for the treatment of a range of cancer and neurodegenerative diseases (49,50). With the knowledge of the acetylation targets and the pathways modulated, new applications for lysine deacetylases may evolve and resulting effects may become more predictable.…”

Section: Prkx Smad4 and Srf) Modulating The Erk1/2 C-jun And P38mentioning

confidence: 99%

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Kraft¹,

Cirstea²,

Voss³

et al. 2011

J. Clin. Invest.

112

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Epigenetic regulation of gene expression, through covalent modification of histones, is a key process controlling growth and development. Accordingly, the transcription factors regulating these processes are important targets of genetic diseases. However, surprisingly little is known about the relationship between aberrant epigenetic states, the cellular process affected, and their phenotypic consequences. By chromosomal breakpoint mapping in a patient with a Noonan syndrome-like phenotype that encompassed short stature, blepharoptosis, and attention deficit hyperactivity disorder, we identified haploinsufficiency of the histone acetyltransferase gene MYST histone acetyltransferase (monocytic leukemia) 4 (MYST4), as the underlying cause of the phenotype. Using acetylation, whole genome expression, and ChIP studies in cells from the patient, cell lines in which MYST4 expression was knocked down using siRNA, and the Myst4 querkopf mouse, we found that H3 acetylation is important for neural, craniofacial, and skeletal morphogenesis, mainly through its ability to specifically regulating the MAPK signaling pathway. This finding further elucidates the complex role of histone modifications in mammalian development and adds what we believe to be a new mechanism to the pathogenic phenotypes resulting from misregulation of the RAS signaling pathway.

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Section: Prkx Smad4 and Srf) Modulating The Erk1/2 C-jun And P38mentioning

confidence: 99%

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Kraft¹,

Cirstea²,

Voss³

et al. 2011

J. Clin. Invest.

112

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“…Preclinical and early clinical trials of HDAC inhibitors have achieved variable efficacy (Lane and Chabner, 2009;Ma et al, 2009;Marks and Xu, 2009), and SAHA (vorinostat) and romidepson have recently been approved for treatment of refractory cutaneous T-cell lymphoma (Monneret, 2007;Grant et al, 2010). Although treatment of cancer has been the primary target for the clinical development of HDAC inhibitors, administration of HDAC inhibitors has also shown beneficial effects in some noncancer disorders, such as sickle cell anemia, muscular dystrophy, neurodegenerative diseases, and inflammatory disorders (Wiech et al, 2009). In addition, an inhibitory effect of TSA on hepatic fibrosis has been reported by Niki et al (1999).…”

Section: Hdac Inhibitors and Their Applicationsmentioning

confidence: 99%

Histone Deacetylase: A Potential Therapeutic Target for Fibrotic Disorders

Pang

Zhuang²

2010

J Pharmacol Exp Ther

162

138

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Histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. In the past several years, the role of HDACs in cancer initiation and progression, as well as the therapeutic effects of HDAC inhibitors in various types of cancer, has been well studied. Recent studies indicated that HDAC activity is also associated with the development and progression of some chronic diseases characterized by fibrosis, including chronic kidney disease, cardiac hypertrophy, and idiopathic pulmonary fibrosis. Here, we review what is known about HDACs in the progression of tissue fibrosis and the potential applications of HDAC inhibitors in the treatment of disorders associated with fibroblast activation and proliferation.

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“…This wide range of activities, together with the fact that HDACs have been found to be druggable targets for cancer and many other disorders (7,9), has led to an intense research effort, including the development of inhibitors to regulate their activity. Current HDAC inhibitors (HDACi) belong to one of four structural classes: hydroxamates, cyclic peptides, aliphatic acids, or benzamides.…”

mentioning

confidence: 99%

“…Therefore, the potential mechanism of HDAC inhibition on the NPC phenotype is not well-understood. Starting from our previous interest in HDACi (7,28) and NPC disease (21,29,30), we investigated the effect of HDACi on cholesterol homeostasis in human NPC mutant fibroblasts.…”

mentioning

confidence: 99%

Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts

Pipalia

Cosner

Huang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

175

227

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Niemann-Pick type C (NPC) disease is predominantly caused by mutations in the NPC1 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles. We report the use of a series of small molecule histone deacetylase (HDAC) inhibitors in tissue culture models of NPC human fibroblasts. Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the NPC1 I1061T mutation, and for several of the inhibitors, correction is associated with increased expression of NPC1 protein. Increased NPC1 I1061T protein levels may partially account for the correction of the phenotype, because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes. The HDAC inhibitor treatment is ineffective in an NPC2 mutant human fibroblast line. Analysis of the isoform selectivity of the compounds used implicates HDAC1 and/or HDAC2 as likely targets for the observed correction, although other HDACs may also play a role. LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the blood–brain barrier and is currently in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM. The findings that HDAC inhibitors can correct cholesterol storage defects in human NPC1 mutant cells provide the potential basis for treatment options for NPC disease.

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Inhibition of Histone Deacetylases: A Pharmacological Approach to the Treatment of Non-Cancer Disorders

Cited by 66 publications

References 104 publications

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice

Histone Deacetylase: A Potential Therapeutic Target for Fibrotic Disorders

Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts

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