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

Current chemotherapeutic and butyrate therapeutics that induce fetal hemogl obin expression generally also suppress erythropoiesis, limiting the produc tion of cells containing fetal hemoglobin (F cells). Recently, selected sho rt-chain fatty acid derivatives (SCFADs) were identified that induce endoge nous gamma -globin expression in K562 cells and human burst-forming units-e rythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3-dependent hematopoietic cell line. In this re port, gamma -globin inducibility by these SCFADs was further demonstrated i n mice transgenic for the locus control region and the entire beta -globin gene locus in a yeast artificial chromosome and in 2 globin promoter-report er assays. Conditioned media experiments strongly suggest that their prolif erative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these com pounds induce prolonged expression of the growth-promoting genes c-myb and c-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolong ed signal transducer and activator of transcription (STAT)-5 phosphorylatio n and activation, and c-cis expression, persisting for more than 120 minute s, whereas with IL-3 alone phosphorylation disappeared within minutes. In c ontrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21(Waf/Cip), which me diates the suppression of cellular growth by butyrate. These findings sugge st 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. (Blood. 2001;97:325 9-3267) (C) 2001 by The American Society of Hematology.