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Tumor Suppressors Klotho and 1,25‐Dihydroxyvitamin D 3 Cooperate via Synergistic Inhibition of Oncogenic Wnt/β‐Catenin Signaling
Author(s) -
Khan Zainab,
Khan Sameera,
Sandoval Ruby,
Whitfield G. Kerr,
Haussler Mark R.,
Jurutka Peter W.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.11
Subject(s) - wnt signaling pathway , calcitriol receptor , signal transduction , microbiology and biotechnology , biology , catenin , transcription factor , beta catenin , vitamin d and neurology , chemistry , biochemistry , endocrinology , gene
The human klotho gene encodes a protein that can generate two isoforms: a single‐pass transmembrane protein (mKlotho) or a secreted peptide (sKlotho) formed from the cleavage of the former. The two isoforms likely possess physiologically unique roles, as mKlotho is known to serve as a membrane‐bound coreceptor for FGF23, while sKlotho may function as an endocrine factor and/or as an enzyme that modifies glycans of cell surface glycoproteins. Due to its putative interactions with several intracellular signaling pathways, klotho has been proposed as an anti‐aging protein and tumor suppressor gene. Intracellular signaling may potentially involve the vitamin D and the Wnt/β‐catenin pathways. Vitamin D, a bioactive lipid and essential nutrient, is acquired via endogenous synthesis upon skin exposure to UVB‐radiation or through dietary intake. Activated 1,25‐dihydroxyvitamin D 3 (1,25D) binds to and stimulates the nuclear vitamin D receptor (VDR), which acts as a central factor in bone and mineral homeostasis, as well as a potential chemopreventative agent through its ability to promote cellular differentiation, while inhibiting growth and division. In contrast, the Wnt/β‐catenin signaling pathway can drive enhanced cellular proliferation leading to numerous types of cancers, especially colorectal neoplasia. We hypothesized that sKlotho and vitamin D/VDR may function collectively to inhibit the tumor‐inducing properties of the β‐catenin pathway and that sKlotho may modulate VDR activity. In order to assess the influences of sKlotho and 1,25D on VDRE‐mediated transcription and Wnt/β‐catenin signaling, transcriptional assays and quantitative real time PCR (qPCR) were conducted in embryonic kidney (HEK293) and colon cancer (HCT116) cell lines. We also analyzed the effects of an NAD‐dependent deacetylase sirtuin‐1 (SIRT1), a potential VDR modulator that is activated by resveratrol, on the β‐catenin signaling pathway. Our results revealed an increase in the transactivation capacity of VDR in the presence of 1,25D, SIRT1, and sKlotho. Additionally, sKlotho, SIRT1 and 1,25D were shown to independently and synergistically inhibit β‐catenin activity. The data also indicated functional differences between the two isoforms of klotho, as mKlotho was shown to enhance β‐catenin activity, suggesting that the proposed anti‐aging effects of klotho are presumably directed by the secreted isoform. In conclusion, our study suggests a role for sKlotho as a tumor suppressor and further points to the potential for molecular crosstalk between vitamin D and klotho signaling to elicit optimal human health. Support or Funding Information National Institutes of Health Grants DK033351 to MRH and CA140285 to PWJ