SLC5A8 (Solute carrier family 5, member 8), proposed to be a potential tumor suppressor gene, is down-regulated by epigenetic changes in some
colorectal cancer cells, and ectopic expression of SLC5A8 in SLC5A8-deficient
colon cancer cell lines leads to suppression of the colony-forming ability of these cells.
Activin A, a member of the
transforming growth factor-β (TGF-β) superfamily, has been shown to inhibit the proliferation of a variety of
tumor (and normal) human cell types. However, the mechanism(s) by which
activin A exerts its inhibitory effects are not yet understood. In this study, we showed that
activin A up-regulated SLC5A8 expression in
colorectal cancer RKO cells and human embryonic kidney (HEK) 293T cells. To elucidate the underlying mechanism involved in this process, we investigated the activation of the Smad signaling pathway, and analyzed the effects of dominant negative Smad3 and Smad2
proteins on
activin A-induced SLC5A8 expression. The results indicated that
activin A-induced SLC5A8 expression was dependent on activation of Smad3. Further analysis showed that
activin A induced SLC5A8 expression via transcriptional activation. Deletion analysis indicated that the CAGA elements located within the -273/-222 region of the human SLC5A8 promoter were responsive to
activin A. Taken together, our results strongly suggest that
activin A up-regulates SLC5A8 expression through the Smad signaling pathway, which also partially explains the inhibitory effects of
activin A in RKO cells.