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.