Abstract
CD82 acts as a tumor suppressor in a series of steps in malignant progression. Here, we identified a novel function of CD82 on posttranslational regulating E-cadherin in prostate cancer. In our study, the declined expression of CD82 was verified in prostate cancer tissues and cell lines compared with normal tissue and cell lines. Functionally, CD82 inhibited cell migration and E-cadherin cleavage from the cell membrane in prostate cancer cell. Further study proved that a disintegrin and metalloproteinase ADAM17 as an executor of E-cadherin cleavage mediated the inhibitory regulation of CD82 in E-cadherin shedding in prostate cancer. Specifically, CD82 interacted with ADAM17 and inhibited its metalloprotease activity, which led to the descent of E-cadherin shedding. These results show a nuanced but important role of CD82 in nontranscriptional regulation of E-cadherin, which may help to understand the intricate regulation of dysfunctional adhesion molecule in cancer progression.
Highlights
According to the recent cancer statistics, prostate cancer was the second most frequent cancer and the fifth leading cause of cancer death in men worldwide [1]
Since CD82 is located through the cell membrane and most of its functions resorted to the tetraspanin-enriched membrane microdomains (TEM) [15], we focused on the proteolytic modification to unveil the function of CD82 on posttranslational regulation of E-cadherin, which may improve our understanding of the metastatic suppressor role of CD82 and get much more details on the metastasis progress of prostate cancer
To explore the mechanism referring to CD82-mediated E-cadherin shedding, we reviewed the related researches and screened four A disintegrin and metalloprotease (ADAM) candidates which had been reported as protease of cadherin ( E-cadherin) [16,17,18,19, 36]
Summary
According to the recent cancer statistics, prostate cancer was the second most frequent cancer and the fifth leading cause of cancer death in men worldwide [1]. As a key adhesive molecule in the prevention of tumor progression, E-cadherin undergoes a series of negative regulations in multiple tumors, including mutations [2, 3], epigenetic silencing [4, 5], transcriptional regulation [6], and endocytosis [7] Besides those above, as a membrane protein, E-cadherin was processed through proteolytic modification. CD82 was found to inhibit tumor metastasis [8] as well as cell death [9], senescence [10], angiogenesis [11], and so on It belongs to the superfamily of tetraspanins, which interact with adjacent membrane proteins and cytoplastic factors to regulate their functions such as integrins and receptor tyrosine kinase (RTK) [12, 13]. Since CD82 is located through the cell membrane and most of its functions resorted to the tetraspanin-enriched membrane microdomains (TEM) [15], we focused on the proteolytic modification to unveil the function of CD82 on posttranslational regulation of E-cadherin, which may improve our understanding of the metastatic suppressor role of CD82 and get much more details on the metastasis progress of prostate cancer
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