Activin A induces SLC5A8 expression through the Smad3 signaling pathway in human colon cancer RKO cells.
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.
Zhang
Yu
Y
National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
Bao
Yong-Li
YL
Yang
Mei-Ting
MT
Wu
Yin
Y
Yu
Chun-Lei
CL
Huang
Yan-Xin
YX
Sun
Ying
Y
Zheng
Li-Hua
LH
Li
Yu-Xin
YX
D028341:Activins / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D027501:Monocarboxylic Acid Transporters; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human; D051900:Smad3 Protein; C422405:activin A; D028341:Activins