Nuclear Syndecan-1 Regulates Epithelial-Mesenchymal Plasticity in Tumor Cells

Abstract

Tumor cells undergoing epithelial-mesenchymal transition (EMT) lose cell surface adhesion molecules and gain invasive and metastatic properties. EMT is a plastic process and tumor cells may shift between different epithelial-mesenchymal states during metastasis. However, how this is regulated is not fully understood. Syndecan-1 (SDC1) is the major cell surface proteoglycan in epithelial cells and has been shown to regulate carcinoma progression and EMT. Recently, it was discovered that SDC1 translocates into the cell nucleus in certain tumor cells. Nuclear SDC1 inhibits cell proliferation, but whether nuclear SDC1 contributes to the regulation of EMT is not clear. Here, we report that loss of nuclear SDC1 is associated with cellular elongation and an E-cadherin-to-N-cadherin switch during TGF-β1-induced EMT in human A549 lung adenocarcinoma cells. Further studies showed that nuclear translocation of SDC1 contributed to the repression of mesenchymal and invasive properties of human B6FS fibrosarcoma cells. The results demonstrate that nuclear translocation contributes to the capacity of SDC1 to regulate epithelial-mesenchymal plasticity in human tumor cells and opens up to mechanistic studies to elucidate the mechanisms involved.

Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness

“…Moreover, silencing of SDC1 leads to increased N-cadherin, nuclear localization of ZEB1, and invasion. The observed role of SDC1 strengthens the view about its involvement in modulation of EMP [ 115 ]. Finally, in invasive ductal carcinoma in situ cells, SDC1 gene silencing leads to the upregulation of several markers of EMT, such as the epithelial markers claudin and E-cadherin, the mesenchymal marker fibronectin, as well as the invasive markers MMP-3, MMP-9, and HPSE.…”

Circulating syndecan-1 and glypican-4 predict 12-month survival in metastatic colorectal cancer patients

“…Syndecan-1 (SDC1, alias CD138) is the major cell-surface proteoglycan in endothelial cells ( 9 , 10 ) and is involved in the remodeling and angiogenesis of CRC tissue ( 11 ). Loss of SDC1 expression in CRC cells has been associated with metastatic potential and shorter survival in several ( 11 – 13 ) but not all studies ( 14 ).…”

The Role and Therapeutic Value of Syndecan-1 in Cancer Metastasis and Drug Resistance

“…A positive correlation between Snail expression and nuclear SDC-1 translocation was reported in prostate cancer cells ( Farfán et al, 2020 ); cells overexpressing Snail exhibited increased nuclear SDC-1 levels in comparison with cytoplasmic concentrations ( Millanes-Romero et al, 2013 ). The nuclear translocation of SDC-1, however, was also reported to facilitate elimination of mesenchymal and invasive characteristics among human B6FS fibrosarcoma cells, with loss of nuclear SDC-1 related to cell elongation and E- to N-cadherin switching during the TGF-β1-induced EMT in human A549 lung cancer cells ( Kumar-Singh et al, 2021 ). The influence of intranuclear SDC-1 thus likely differs between different tumors and further study is required to elucidate how nuclear SDC-1 controls the EMT.…”