The Role of Deubiquitinases in Tumor Epithelial-mesenchymal Transition / 中国生物化学与分子生物学报

ABSTRACT

Tumor invasion and metastasis are the main reasons for the tumor deterioration and the cause of poor prognosis of patients. In recent years a vast amount of research has been reported that epithelial-mesenchymal transition (EMT) in cancer cells plays a critical role in tumor metastasis. Moreover, EMT is also closely related to tumor stemness, tumor drug resistance and other tumor malignant behaviors. Therefore, effective suppression of EMT has been investigated as potential therapeutic strategy for the treatment of tumor. One of the main functions of the deubiquitinating enzymes (DUBs) is to maintain the dynamic balance of intracellular protein levels via removing conjugated ubiquitin from target proteins, which in turn avoids degradation of target proteins through the ubiquitin protease pathway. DUBs are a class of proteins responsible for regulating protein ubiquitination modification, which abnormal expression or alterations of enzyme activity often results in the initiation of many diseases, including a variety of cancers. Numerous studies have found that some DUBs are unbalanced in the process of tumor invasion and metastasis, and play important roles in the process of tumor metastasis. EMT refers to the dynamic cellular process of transforming epithelial cells to mesenchymal cells, which involves changes in the expression levels of various molecular markers, such as EMT-related transcription factors (Snial1, Slug, ZEB1 etc.), and cell surface proteins (E-cadherin, N-cadherin etc.). Generally, these associated proteins are unstable and easily degraded, meanwhile the occurrence of the EMT process involves the regulation of protein stability. DUBs, as a class of enzymes that maintain protein stability, play important roles in regulating the stability of EMT-related proteins. The occurrence of EMT is also inseparable from the abnormal activation of many signaling pathways in cells such as TGF-β and Wnt pathways. DUBs mediate the activation of these pathways to indirectly regulate the occurrence and development of EMT. DUBs can directly or indirectly affect the progress of EMT by regulating EMT-related molecules or signaling pathways. Therefore, targeting DUBs to inhibit tumor invasion and metastasis will provide new methods and programs for tumor treatment. This review mainly discusses the important roles of DUBs in the EMT process to elucidate that DUBs play critical roles in regulating EMT-related molecules and signal pathways, and may serve as potential therapeutic targets for cancers.