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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3259-3267
RED CELLS
Short-chain fatty acid derivatives stimulate cell proliferation
and induce STAT-5 activation
Michael S. Boosalis,
Ram Bandyopadhyay,
Emery H. Bresnick,
Betty S. Pace,
Karyn Van DeMark,
Baohua Zhang,
Douglas V. Faller, and
Susan
P. Perrine
From the Departments of Medicine, Pediatrics,
Pharmacology, and Experimental Therapeutics, Cancer Research Center and
Hemoglobinopathy-Thalassemia Research Unit, Boston University School of
Medicine, Boston, MA; the Department of Pharmacology, University of
Wisconsin Medical School, Madison, WI; and the Department of Structural
and Cellular Biology, University of Southern Alabama, Mobile, AL.
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
p21Waf/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.
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