The proteoglycan decorjn induces tumor suppression via upregulation of p21, an inhibitor of cyclin dependent kinases

Several key molecules in cancer development are proteins that operate outside the nucleus and often interact at the cell-matrix boundaries either by detecting changes in the extracellular environment or by relaying messages to their control machineries. Under the appropriate circumstances, the latter genes may act as tumor suppressor genes. Decorin, a member of the small leucine-rich proteoglycan gene family, interacts with a variety of growth factors and proteins thereby modulating their biological activities. This proteoglycan has been implicated in the negative control of cell proliferation by several observations. Decorin expression is upregulated 1040 fold in quiescence but suppressed in virally-transformed and in several tumor cell lines via methylation of its genomic control regions. Overexpression of decorin in CHO cells leads to growth suppression via a block of TGF-β, whereas de novo expression of decorin in human colon carcinoma cells abrogates the malignant phenotype by arresting the cells in G,. Here we show that this decorin-induced G, block is associated with upregulation of p21 in a TGF-β- and p53-independent pathway. This leads to suppression of cyclin-dependent kinase activity and subsequent block of cell division, thus providing a plausible mechanism by which decorin may directly induce growth suppression of colon cancer cells in vivo.