Sodium butyrate down-regulates tristetraprolin-mediated cyclin B1 expression independent of the formation of processing bodies.

Butyrate regulates multiple host cellular events including the cell cycle; however, little is known about the molecular mechanism by which butyrate induces a global down-regulation of the expression of genes associated with the cell cycle. Here, we demonstrate that treating HEK293T cells and the non-small-cell lung cancer cell line A549 with a high concentration of sodium butyrate reduces cyclin B1 expression. The underlying mechanism is related to the destabilization of its mRNA by tristetraprolin, which is up-regulated in response to sodium butyrate. Specifically, the sodium butyrate stimulation reduces the mRNA and protein expression of cyclin B1 and, conversely, upregulates tristetraprolin expression. Importantly, the overexpression of tristetraprolin in HEK293T decreases the mRNA and protein expression of cyclin B1; in contrast, knockdown of tristetraprolin mediated by small interfering RNA increases its expression in response to sodium butyrate treatment for both HEK293T and A549 cells. Furthermore, results from luciferase reporter assays and RNA immunoprecipitation indicate that sodium butyrate accelerates 3' UTR-dependent cyclin B1 decay by enhancing the binding of tristetraprolin to the 3' untranslated region of cyclin B1. Surprisingly, the overexpression of tristetraprolin prevents the formation of processing bodies, and the siRNA-mediated silencing of EDC4 does not restore the sodium butyrate-induced reduction of cyclin B1 expression. Thus, we confirm that NaBu regulates ZFP36-mediated cyclin B1 expression in a manner that is independent of the formation of P-bodies. The above findings disclose a novel mechanism of sodium butyrate-mediated gene expression regulation and might benefit its application in tumor treatment.