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Butyrate is a short chain fatty acid produced in the human colon by bacterial fermentation of carbohydrates such as dietary fibre. 1 The large amounts produced are physiologically important for the colonic mucosa. Indeed, butyrate is the major energy substrate for colonic epithelial cells and is also known to exert various biological effects on cultured mammalian cells, including inhibition of cell proliferation and induction of differentiation. 2 3 Its therapeutic potential in colon cancer has also been proposed. 4 5
The mechanisms by which butyrate regulates cell proliferation/differentiation are still unclear, although it is known to block cell proliferation, mainly in the G1 phase of the cell cycle. 6 Moreover, our previous studies showed that butyrate action is related to p21/WAF1/Cip1 stimulation and cyclin D expression. 7
The most commonly reported mechanism by which butyrate modulates gene expression involves an alteration of chromatin structure subsequent to increased histone acetylation. Butyrate is a potent inhibitor of histone deacetylase, which leads to histone hyperacetylation. 8 9 It is generally assumed that histone hyperacetylation results in relaxation of the chromatin structure, thereby making DNA accessible to a variety of transcription factors. 10 11 A cDNA encoding a human histone deacetylase catalytic subunit has been cloned, the predicted protein sequence of which is very similar to a yeast transcriptional regulator. 12 This finding confirms that histone deacetylase is an important regulator of eukaryotic transcription. A variety of biological phenomena such as cell cycle blockade and/or differentiation induced by butyrate may be ascribed to this histone hyperacetylation process. However, the role of histone acetylation in butyrate related biological effects needs to be clarified.
Trichostatin A is structurally unrelated to butyrate and was originally reported to be a fungistatic antibiotic. It can cause potent reversible inhibition of mammalian histone deacetylase at nanomolar concentrations both in vivo and in vitro, 13 appreciable induction of Friend leukaemia cell differentiation, 14 and inhibition of cell cycle progression in rat fibroblasts. 15 It appears to be a promising tool for analysing the many functions of histone hyperacetylation in cell proliferation and differentiation. For example, it reproduced the amplification of a viral transgene product achieved with butyrate in cells infected with E1 defective adenovirus, and it has been shown that inhibitors of histone deacetylase-for...