[Frontiers in Bioscience 14, 453-462, January 1, 2009]

Epigenetic regulation of cystatins in cancer

Ashley G. Rivenbark, William B. Coleman

Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599


1. Abstract
2. Epigenetic mechanisms of gene silencing in cancer
3. Cysteine protease inhibitors - cystatins
4. Cystatin super-family
5. Cystatin A (Stefin A)
5.1. Structure and function
5.2. Cystatin A in cancer
5.3. Epigenetic regulation of cystatin A
6. Cystatin B (Stefin B)
6.1. Structure and function
6.2. Cystatin B in cancer
6.3. Epigenetic regulation of cystatin B
7. Cystatin C
7.1. Structure and function
7.2. Cystatin C in cancer
7.3. Epigenetic regulation of cystatin C
8. Cystatin M
8.1. Structure and function
8.2. Cystatin M in cancer
8.3. Epigenetic regulation of cystatin M
9. Conclusions and perspectives
10. Acknowledgements
11. References


Cystatins function as cysteine protease inhibitors, are expressed in numerous cell types, and regulate a number of physiological processes. Four cystatins have been extensively studied: cystatin A, cystatin B, cystatin C, and cystatin M. Aberrant regulation of cystatins occurs 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 and cancer cells exhibit aberrant epigenetic events (such as DNA methylation), leading to gene silencing. Cystatins 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.