Epigenetic regulation of cystatins in cancer

Cystatins function as cysteine protease inhibitors, are expressed in numerous cell types, and regulate a number of physiological processes. The cystatin superfamily consists of 12 members that divide into three types based on protein structure, location in the body, and physiological role. Four cystatin family members have been extensively studied: cystatin A, cystatin B, cystatin C, and cystatin M. Aberrant regulation of cystatin family members has been noted in a number of diseases, including cancer and certain neurodegenerative disorders. Recent advances in the understanding of cystatin function suggest that these proteins may regulate promotion or suppression of tumor growth, invasion, and metastasis. Cancer is a disease of abnormal gene expression characterized by inappropriate expression of positive mediators of cell proliferation in conjunction with diminished expression of negative mediators of cell growth. Cancer cells of many different human neoplasms exhibit aberrant epigenetic events (such as DNA methylation), which lead to gene silencing. Members of the cystatin family are epigenetically silenced through DNA methylation-dependent mechanisms in several forms of cancer, including breast, pancreatic, brain, and lung. These findings suggest that DNA methylation-dependent epigenetic mechanisms may play an important role in the loss of cystatin gene expression and protein function during neoplastic transformation and/or tumor progression. This review summarizes the biological processes in which cystatins function, focuses on the neoplastic events that involve aberrant regulation of cystatins, and discusses the possible epigenetic regulation of cystatins in cancer.