Abstract
Cystatin D (CST5) encodes an inhibitor of cysteine proteases of the cathepsin family and is directly induced by the vitamin D receptor (VDR). Interestingly, vitamin D3 exerts tumor suppressive effects in a variety of tumor types. In colorectal cancer (CRC) cells CST5 was shown to mediate mesenchymal-epithelial transition (MET). Interestingly, vitamin D3 was shown to exert tumor suppressive effects in a variety of tumor types, including colorectal cancer (CRC). We recently performed an integrated genomic and proteomic screen to identify targets of the p53 tumor suppressor in CRC cells. Thereby, we identified CST5 as a putative p53 target gene. Here, we validated and characterized CST5 as a direct p53 target gene. After activation of a conditional p53 allele, CST5 was upregulated on mRNA and protein levels. Treatment with nutlin-3a or etoposide induced CST5 in a p53-dependent manner. These regulations were direct, since ectopic and endogenous p53 occupied a conserved binding site in the CST5 promoter region. In addition, treatment with calcitriol, the active vitamin D3 metabolite, and simultaneous activation of p53 resulted in enhanced CST5 induction and increased repression of SNAIL, an epithelial-mesenchymal transition (EMT) inducing transcription factor. Furthermore, CST5 inactivation decreased p53-induced mesenchymal-epithelial transition (MET) as evidenced by decreased inhibition of SNAIL and of migration by p53. Furthermore, CST5 expression was directly repressed by SNAIL. In summary, these results imply CST5 as an important mediator of tumor suppression by p53 in colorectal cancer. In addition, they suggest that a combined treatment activating p53 and the vitamin D3 pathway may function via induction of CST5.
Highlights
During the last years the role of vitamin D, primarily vitamin D3, in tumor suppression has attracted considerable attention
We showed that CST5 is directly induced by p53, which occupies a canonical p53 binding site upstream of the CST5 promoter
We identified SNAIL as a www.impactjournals.com/oncotarget direct repressor of CST5
Summary
During the last years the role of vitamin D, primarily vitamin D3, in tumor suppression has attracted considerable attention (reviewed in [1,2,3,4]). There is increasing evidence strongly suggesting that vitamin D3 reduces the risk of developing cancer and may be applied for the treatment of cancer as it was shown to induce differentiation and apoptosis, and inhibit proliferation and angiogenesis (reviewed in [5]). Calcitriol binds to the vitamin D receptor (VDR), which regulates the expression of several genes involved in colorectal cancer, such as BIRC5, CDKN1A, CDH1 or HIF1α (reviewed in [5]). Calcitriol-induced expression of cystatin D (CST5) was shown to inhibit proliferation, migration, anchorageindependent growth as well as tumor formation of xenografted colorectal cancer cell lines [25]. We present evidence that a combination of p53 activation and calcitriol treatment results in enhanced CST5 expression and suppression of the EMT transcription factor SNAIL. We demonstrate that SNAIL directly represses CST5 expression and that calcitriol treatment reverses this effect
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