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Title

Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells

AuthorsÁlvarez-Díaz, S.; Valle, Noelia ; García, José M.; Peña, Cristina; Freije, José M. P.; Quesada, Víctor; Astudillo, Aurora; Bonilla, Félix; López-Otín, Carlos; Muñoz Terol, Alberto
Issue DateAug-2009
PublisherAmerican Society for Clinical Investigation
CitationJournal of Clinical Investigation 119(8): 2343-2358 (2009)
AbstractThe active vitamin D metabolite 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] has wide but not fully understood antitumor activity. A previous transcriptomic analysis of 1α,25(OH)2D3 action on human colon cancer cells revealed cystatin D (CST5), which encodes an inhibitor of several cysteine proteases of the cathepsin family, as a candidate target gene. Here we report that 1α,25(OH)2D3 induced vitamin D receptor (VDR) binding to, and activation of, the CST5 promoter and increased CST5 RNA and protein levels in human colon cancer cells. In cells lacking endogenous cystatin D, ectopic cystatin D expression inhibited both proliferation in vitro and xenograft tumor growth in vivo. Furthermore, cystatin D inhibited migration and anchorage-independent growth, antagonized the Wnt/β-catenin signaling pathway, and repressed c-MYC expression. Cystatin D repressed expression of the epithelial-mesenchymal transition inducers SNAI1, SNAI2, ZEB1, and ZEB2 and, conversely, induced E-cadherin and other adhesion proteins. CST5 knockdown using shRNA abrogated the antiproliferative effect of 1α,25(OH)2D3, attenuated E-cadherin expression, and increased c-MYC expression. In human colorectal tumors, expression of cystatin D correlated with expression of VDR and E-cadherin, and loss of cystatin D correlated with poor tumor differentiation. Based on these data, we propose that CST5 has tumor suppressor activity that may contribute to the antitumoral action of 1α,25(OH)2D3 in colon cancer.
Description16 pages, 11 figures.
Publisher version (URL)http://dx.doi.org/10.1172/JCI37205
URIhttp://hdl.handle.net/10261/24884
DOI10.1172/JCI37205
ISSN0021-9738
Appears in Collections:(IIBM) Artículos
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