Nuclear Cystatin D has antitumor gene regulatory effects in colon cancer cells

Abstract

Cystatin D is a member of the cystatin superfamily of inhibitors of cathepsins, cysteine proteases that degrade multiple targets including adhesion proteins, matrix components and other proteases. Cystatins play multiple roles in physiology and pathology, including tumorigenesis and neurodegenerative disorders, and a number of cathepsins are thought to be involved in cancer and other diseases as regulators of a variety of biochemical processes. Preferential attention has been paid to the deregulation and imbalance between cathepsins and cystatins in invasion and metastasis of several neoplasias. We have previously reportad that cystatin D prometes cell adhesion and decreases proliferation. migration and invasion of colon carcinoma cells. lt is downregulated during human colon carcinogenesis, and considerad as a candidate tumor suppressor gene that is transcriptionally induced by 1,25(OH)2D3, the most active metabolite of vitamin D, mediating its protective effects against this neoplasia (Álvarez-Díaz et al., J. Clin. lnvest., 2009). The finding that mutant forms of cystatin D with no protease inhibitory activity lack the antimigratory but not the antiproliferative effect on colon cancer cells indicates that cystatin D has cathepsin-independent mechanism(s) of action. Cathepsins have traditionally been considerad endosomal/lysosomal or secreted proteases; however, new evidences support their localization in other cellular compartments. Recent studies have reported the activity of cathepsin L. a cystatin D target, within the cell nucleus. Analogously, a few cystatins and other protease inhibitors have been found to act in the nuclear compartment. Taken together, these findings prompted us to investigate in depth the mechanism of action of cystatin D in colon carcinoma cells.