Short-chain fatty acids induce γ-globin gene expression by displacement of a HDAC3-NCoR repressor complex

Mankidy, Rishikesh; Faller, Douglas V.; Mabaera, Rodwell; Lowrey, Christopher H.; Boosalis, Michael S.; White, Gary L.; Castañeda, Serguei A.; Perrine, Susan P.

doi:10.1182/blood-2005-12-010934

Cited by 49 publications

(64 citation statements)

References 37 publications

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“…One such compound, 2,2-dimethylbutyrate sodium salt (HQK-1001) was found to stimulate g-globin production and erythropoiesis in vitro and in animal models at concentrations that could be achievable in humans with convenient oral dosing [25]. The molecular mechanism of action of HQK-1001 is not fully elucidated but it is believed to reactivate the g-globin gene by inducing a dissociation of HDAC3 and its adaptor protein nuclear receptor co-repressor (NCoR) from the g-globin gene promoter, with coincidental recruitment of RNA polymerase II to the g-globin gene promoter [26]. HQK-1001 also enhances erythropoiesis by phosphorylation and activation of STAT-5, c-cis, and Bcl-xL [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

et al. 2013

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-dimethylbutyrate (HQK-1001), an orally-bioavailable promoter-targeted fetal globin gene-inducing agent, was evaluated in an open-label, randomized dose-escalation study in 52 subjects with hemoglobin SS or S/b 0 thalassemia. HQK-1001 was administered daily for 26 weeks at 30 mg/kg (n 5 15), 40 mg/kg (n 5 18) and 50 mg/kg (n 5 19), either alone (n 5 21) or with hydroxyurea (n 5 31). The most common drug-related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose-limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non-compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases 4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8-3.2%] in 21 subjects receiving HQK-1001 alone and 2.7% (95% CI, 1.7-3.8%) in 31 subjects receiving HQK-1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5-1.0 g/dL), and 13 subjects (25%) had increases 1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK-1001 in sickle cell disease. Am. J. Hematol. 88:E255-E260, 2013.

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Section: Introductionmentioning

confidence: 99%

A dose‐escalation phase IIa study of 2,2‐dimethylbutyrate (HQK‐1001), an oral fetal globin inducer, in sickle cell disease

et al. 2013

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“…Knockdown of HDAC3 by siRNA was shown to induce the expression of the γ-globin gene. These results suggest that from all the HDACs expressed in erythroid cells, HDAC3 might be the isoform that is primarily responsible for γ-globin silencing (Mankidy et al, 2006). In addition to their effects on HDAC activity and histone acetylation status, HDACi exert additional biological functions.…”

Section: Epigenetic Modifications and Hbf Synthesismentioning

confidence: 93%

Histone deacetylase inhibitors and hemoglobin F induction in β-thalassemia

Migliaccio

Rotili

Nebbioso

et al. 2008

The International Journal of Biochemistry & Cell Biology

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Epigenomic modifiers, such as histone deacetylase inhibitors, are compounds that regulate gene expression by interfering with the enzymatic machinery that maintains the proper chromatin structure of the nucleus. These compounds are at the forefront of novel therapeutic agents for the treatment of several diseases including cancer and genetic disorders such as β-thalassemia and sickle cell disease.Here we review the current understanding of the mechanism of action of epigenomic modifiers in the treatment of β-thalassemia and sickle cell anemia. We also discuss how the lessons learned from the study of the effects of these compounds on the β-globin locus, one of the best characterized regions of the human genome, might contribute to the understanding of the mechanism of action of these same compounds in cancer, where the specific regions of the genome that are responsible for the pathophysiology of the disease are often poorly defined.

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“…Particularly, one of these compounds, RB7, exhibited a high capacity to stimulate HbF synthesis in cultured erythroid progenitors [113]. Molecular studies have shown that RB7 induces dissociation of HDCAC3 and its adaptor protein NCor, from the γ-globin gene promoter, thus promoting the coincident and proportions recruitment of RNA polymerase II to this promoter [113].…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%