The Role of Alpha-Klotho as a Universal Tumor Suppressor.

The klotho gene is implicated in many physiological activities, among them aging, glucose metabolism, and phosphate and calcium metabolism. Many cellular activities of klotho were implicated in promoting these activities. Two of them, inhibition of the insulin-like growth factor-1 pathway and of the Wnt signaling pathway, are also major pathways associated with cancer development and progression. These discoveries prompted a surge of research aiming to elucidate the role of klotho in cancer. Studies show that klotho is universally silenced in a wide array of malignancies, including breast, pancreatic, ovarian, lung, colorectal, and melanoma, and that klotho's expression can serve as an invaluable prognostic marker. Epigenetic mechanisms, ie, promoter hypermethylation and histone deacetylation, are mainly associated with klotho's silencing; however, different micro-RNAs were also demonstrated to be involved in the process. The activity of klotho on cancer cells growth was also widely investigated, and accumulating data suggest that klotho forced expression or treatment with the soluble protein can inhibit cancer development and progression. Moreover, studies now aim to reveal the specific region in klotho protein that underlies this anticancer activity in order to develop efficient and safe klotho-based medications.