title: 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 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.
authors.affiliation: Department of Medicine, Cancer Research Center and Hemoglobinopathy-Thalassemia Research Unit, Boston University School of Medicine, Boston, MA, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Boosalis
authors.forename: R
authors.initials: R
authors.lastname: Bandyopadhyay
authors.forename: E H
authors.initials: EH
authors.lastname: Bresnick
authors.forename: B S
authors.initials: BS
authors.lastname: Pace
authors.forename: K
authors.initials: K
authors.lastname: Van DeMark
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: D V
authors.initials: DV
authors.lastname: Faller
authors.forename: S P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D006133:Growth Substances / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007377:Interleukin-3 / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins; D010766:Phosphorylation; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D002087:Butyrates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D005232:Fatty Acids, Volatile; D005914:Globins; D006133:Growth Substances; D006657:Histones; D017874:Immediate-Early Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse