Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Abstract

Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous ␥-globin expression in K562 cells and human burst-forming units-erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3-dependent hematopoietic cell line. In this report, ␥-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire ␤-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb and c-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cis expression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21 Waf/Cip , which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and IntroductionButyrate analogs have been of interest as potential therapeutics for the ␤-globin disorders following the demonstration that butyrate could transcriptionally activate developmentally silenced fetal and embryonic globin genes in many experimental conditions. [1][2][3][4][5][6][7][8][9][10][11] In clinical trials, arginine butyrate stimulated hemoglobin F (HbF) synthesis to levels above 20% and induced a nearly 2-fold increase in the amount of HbF/cell and in proportions of red blood cells expressing HbF (F reticulocytes) in patients with sickle cell anemia. [10][11][12] With constant use, however, the activity of the drug in maintaining substantial increases in HbF-containing erythrocytes gradually decreased. 13 We hypothesized that this tachyphylaxis was due to the coincident cellular growth-inhibitory properties of butyrate and developed intermittent or "pulse" regimens (4 days of use per month) to surmount this problem. 12 Although this regimen proved effective, it also imposed severe limitations on the amount of drug that can be delivered to the patient. An orally bioavailable transcriptional inducer of ␥-globin that does not have cellular growth-inhibitory properties and could be administered more frequently to stimulate a further increase in the proportion of HbF-containing cells (F cells) would be therapeutically advantageous for ␤-globin disord...

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

“…Structural studies have revealed the presence of a previously unrecognized fatty acid docked in the ligand-binding domain of HNF4α [31,32], consistent with the finding that fatty acids regulate HNF4α-dependent gene expression [52,53]. Fatty acids may also modulate STAT5 activity [54,55]. We therefore investigated whether fatty acids could modulate the inhibitory cross-talk between HNF4α and STAT5b.…”

Short-term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats

“…To stimulate fetal globin expression, short chain fatty acids (SCFADs) have been used in many experimental therapeutics such as reporter gene assays, transgenic murine, and nonhuman primate models; and in clinical trials (Pace et al 2002;Steinberg and Rodgers 2001;Perrine 2005;Perrine et al 1993;Collins et al 1995;Ikuta et al 1998;Dover, Brusilow, and Charache 1994;Boosalis et al 2001;Vadolas et al 2004;Atweh, Sutton, and Nassif 1999). Sodium phenylbutyrate and arginine butyrate increase total hemoglobin in beta thalassemia patients (Perrine et al 1993;Collins et al 1995;Ikuta et al 1998;Atweh, Sutton, and Nassif 1999;Perrine et al 2005).…”

Regulation of human IL‐18 gene expression: interaction of PU.1 with GC‐box binding protein is involved in human IL‐18 expression in myeloid cells

“…It has been found that sodium butyrate acts as a histone deacetylase (HDAC) inhibitor and induces gene expression through acetylation of histones, which results in chromatin remodeling [35]. On the other hand, it can alter the phosphorylation state of several proteins including mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)-5 [36,37]. These have been proposed as mechanisms by which sodium butyrate regulates variety of genes, besides its effects on growth arrest and differentiation.…”