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Simple Summary  Cystatin M/E is a low molecular mass protein and a potent inhibitor of proteolytic enzymes (cathepsins B, L, V, and legumain). Cystatin M/E participates in epidermal homeostasis and its deregulation is associated with several skin diseases. Cystatin M/E was initially identified as a tumor suppressor in breast cancer. Its gene is epigenetically downregulated and its methylation status holds a prognostic significance. Moreover, it may also serve as a biomarker for clinical diagnosis. This tumor-suppressing role was documented in cutaneous carcinoma, melanoma, lung, cervical, brain, prostate, gastric and renal cancers. Conversely, increased levels of cystatin M/E in triple-negative breast cancer tissues correlate with a higher risk of metastasis and a lower disease-free survival rate. Beside its orthodox tumor-suppressing role, cystatin M/E may operate as a tumor-promoting effector as reported for thyroid, oral and pancreatic cancer and hepatocellular carcinoma. Given its seemingly contradictory results, in-depth analysis of the regulatory mechanisms of the expression and activity of cystatin M/E during tumorigenesis have to be expanded. Likewise, the possible involvement of cystatin M/E in signaling pathways, beside its protease inhibitor function, remains to be scrutinized.    Abstract  Alongside its contribution in maintaining skin homeostasis and its probable involvement in fetal and placental development, cystatin M/E (also known as cystatin 6) was first described as a tumor suppressor of breast cancer. This review aims to provide an update on cystatin M/E with particular attention paid to its role during tumorigenesis. Cystatin M/E, which is related to type 2 cystatins, displays the unique property of being a dual tight-binding inhibitor of both legumain (also known as asparagine endopeptidase) and cysteine cathepsins L, V and B, while its expression level is epigenetically regulated via the methylation of the  CST6  promoter region. The tumor-suppressing role of cystatin M/E was further reported in melanoma, cervical, brain, prostate, gastric and renal cancers, and cystatin M/E was proposed as a biomarker of prognostic significance. Contrariwise, cystatin M/E could have an antagonistic function, acting as a tumor promoter (e.g., oral, pancreatic cancer, thyroid and hepatocellular carcinoma). Taking into account these apparently divergent functions, there is an urgent need to decipher the molecular and cellular regulatory mechanisms of the expression and activity of cystatin M/E associated with the safeguarding homeostasis of the proteolytic balance as well as its imbalance in cancer.

Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions