Molecular targets and signaling pathways regulated by nuclear translocation of syndecan-1

Abstract

BackgroundThe cell-surface heparan sulfate proteoglycan syndecan-1 is important for tumor cell proliferation, migration, and cell cycle regulation in a broad spectrum of malignancies. Syndecan-1, however, also translocates to the cell nucleus, where it might regulate various molecular functions.ResultsWe used a fibrosarcoma model to dissect the functions of syndecan-1 related to the nucleus and separate them from functions related to the cell-surface. Nuclear translocation of syndecan-1 hampered the proliferation of fibrosarcoma cells compared to the mutant lacking nuclear localization signal. The growth inhibitory effect of nuclear syndecan-1 was accompanied by significant accumulation of cells in the G0/G1 phase, which indicated a possible G1/S phase arrest.We implemented multiple, unsupervised global transcriptome and proteome profiling approaches and combined them with functional assays to disclose the molecular mechanisms that governed nuclear translocation and its related functions. We identified genes and pathways related to the nuclear compartment with network enrichment analysis of the transcriptome and proteome. The TGF-β pathway was activated by nuclear syndecan-1, and three genes were significantly altered with the deletion of nuclear localization signal: EGR-1 (early growth response 1), NEK11 (never-in-mitosis gene a-related kinase 11), and DOCK8 (dedicator of cytokinesis 8). These candidate genes were coupled to growth and cell-cycle regulation. Nuclear translocation of syndecan-1 influenced the activity of several other transcription factors, including E2F, NFκβ, and OCT-1. The transcripts and proteins affected by syndecan-1 showed a striking overlap in their corresponding biological processes. These processes were dominated by protein phosphorylation and post-translation modifications, indicative of alterations in intracellular signaling. In addition, we identified molecules involved in the known functions of syndecan-1, including extracellular matrix organization and transmembrane transport.ConclusionCollectively, abrogation of nuclear translocation of syndecan-1 resulted in a set of changes clustering in distinct patterns, which highlighted the functional importance of nuclear syndecan-1 in hampering cell proliferation and the cell cycle. This study emphasizes the importance of the localization of syndecan-1 when considering its effects on tumor cell fate.Electronic supplementary materialThe online version of this article (10.1186/s12860-017-0150-z) contains supplementary material, which is available to authorized users.

Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells

“…Our results further support that EGR1 directly regulates HPSE transcription. Data in fibrosarcoma cells suggest that the nuclear localization of Sdc-1 is a critical factor in regulating EGR1 expression, as expression of Sdc-1 lacking its nuclear localization signal resulted in upregulation of EGR1 (49). Therefore, the upregulation of EGR1 observed in Sdc-1depleted Caco2 cells in our study may have been due to the reduction in nuclear, Sdc-1.…”

The HPA/SDC1 axis promotes invasion and metastasis of pancreatic cancer cells by activating EMT via FGF2 upregulation

“…As previously reported, syndecan-1 (SDC1) is a cell adhesion molecule expressed on the cell surface, which is usually characterized by covalent bonds of heparan sulfate (HS) (4). Ibrahim et al (5) reported the involvement of SDC1 in breast cancer, suggesting that this protein maintains cell phenotype and inhibits cell migration, whereas when SDC1 is isolated from the cell surface, cells may exhibit enhanced proliferative and migratory abilities.…”

Dually modified transmembrane proteoglycans in development and disease

“…However, in the normal murine mammary gland and in human lung carcinoma epithelial cells, SDC1 cell surface expression is upregulated by TGF-β in a post-translational and Protein Kinase A (PKA) dependent manner[146]. Microarray studies from fibrosarcoma cells revealed that nuclear SDC1, promotes TGF-β signaling activity[147]. In mesothelioma cells, however, TGF-β inhibited nuclear translocation of SDC1 to reduce cell proliferation[148].…”