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Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation
M S Boosalis1, R Bandyopadhyay, E H Bresnick
1Department of Medicine, Cancer Research Center and Hemoglobinopathy-Thalassemia Research Unit, Boston University School of Medicine, Boston, MA, USA.
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 gamma-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, gamma-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire beta-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 STAT-5 activation, contribute to the cellular proliferation induced by selected SCFADs.
Insights
Selected short-chain fatty acid derivatives (SCFADs) promote fetal hemoglobin (F cell) production without suppressing erythropoiesis. These SCFADs stimulate hematopoietic cell proliferation by prolonging c-myb, c-myc, and STAT-5 activation.
Area of Science:
- Hematology
- Molecular Biology
- Drug Discovery
Background:
- Current therapies for fetal hemoglobin (F cell) induction often inhibit erythropoiesis, limiting therapeutic efficacy.
- Short-chain fatty acid derivatives (SCFADs) have emerged as potential agents to increase F cells.
Purpose of the Study:
- To investigate the gamma-globin inducibility and proliferative effects of specific SCFADs.
- To elucidate the underlying molecular mechanisms of SCFAD-induced erythroid progenitor proliferation.
Main Methods:
- Demonstration of gamma-globin inducibility in transgenic mice and reporter assays.
- Assessment of SCFADs' effect on hematopoietic cell proliferation and gene expression (c-myb, c-myc, STAT-5, cis).
- Comparative analysis with butyrate regarding histone acetylation and p21(Waf/Cip) induction.
Main Results:
- Selected SCFADs induced gamma-globin expression in vitro and in vivo.
- SCFADs promoted proliferation of erythroid progenitors and hematopoietic cell lines.
- SCFADs induced prolonged activation of STAT-5, c-myb, c-myc, and cis expression.
- Unlike butyrate, SCFADs did not cause bulk histone H4 hyperacetylation or p21(Waf/Cip) induction.
Conclusions:
- Specific SCFADs can induce F cells and stimulate erythropoiesis, offering a potential therapeutic advantage.
- Prolonged STAT-5 activation and induction of growth-promoting genes, without histone hyperacetylation or p21 induction, mediate SCFAD-driven proliferation.