SULF-2: an extracellular modulator of cell signaling and a cancer target candidate

University of California, Department of Anatomy and Comprehensive Cancer Center, San Francisco, 94143, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 09/2010; 14(9):935-49. DOI: 10.1517/14728222.2010.504718
Source: PubMed


Importance of the field: Sulf-1 and Sulf-2 are sulfatases that edit the sulfation status of heparan sulfate proteoglycans (HSPGs) on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers with Sulf-2 in particular implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer and hepatocellular carcinoma. Areas covered in this review: This review describes the novel activity of the Sulfs in altering the sulfation pattern of HSPG chains on the outside of cells. Thereby, the Sulfs can change the binding of growth factors to these chains and can either promote (e.g., Wnt) or inhibit (e.g., fibroblast growth factor-2) signaling. The review focuses on the widespread upregulation of both Sulfs in cancers and summarizes the evidence that Sulf-2 promotes the transformed behavior of several types of cancer cells in vitro as well as their tumorigenicity in vivo. What the reader will gain: Sulf-2 is a bonafide candidate as a cancer-causing agent in NSCLC and other cancers in which it is upregulated. Take home message: Sulf-2 is an extracellular enzyme and as such would be an attractive therapeutic target for the treatment of NSCLC and other cancers.

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    • "Heparan sulfate can also be modified by editing enzymes, such as 6-O-endo-sulfatases and heparanase (Ai et al., 2003; Ilan et al., 2006; Xu et al., 2007). The extracellular 6-O-endo-sulfatases, Sulf1 and Sulf2, selectively remove sulfate groups from the carbon 6 positions (Lamanna et al., 2008; Rosen and Lemjabbar-Alaoui, 2010; Nagamine et al., 2012), while heparanase cleaves HS chains from the protein core, generating free HS (Bernfield et al., 1999; Galvis et al., 2007). "
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    ABSTRACT: Heparan sulfate (HS) is a complex and highly variable polysaccharide, expressed ubiquitously on the cell surface as HS proteoglycans (HSPGs), and found in the extracellular matrix as free HS fragments. Its heterogeneity due to various acetylation and sulfation patterns endows a multitude of functions. In animal tissues, HS interacts with a wide range of proteins to mediate numerous biological activities; given its multiple roles in inflammation processes, characterization of HS in human serum has significant potential for elucidating disease mechanisms. Historically, investigation of HS was limited by its low concentration in human serum, together with the complexity of the serum matrix. In this study, we used a modified mass spectrometry method to examine HS disaccharide profiles in the serum of 50 women with rheumatoid arthritis (RA), and compared our results to 51 sera from healthy women. Using various purification methods and online LC-MS/MS, we discovered statistically significant differences in the sulfation and acetylation patterns between populations. Since early diagnosis of RA is considered important in decelerating the disease’s progression, identification of specific biomolecule characterizations may provide crucial information towards developing new therapies for suppressing the disease in its early stages. This is the first report of potential glycosaminoglycan biomarkers for RA found in human sera, while acknowledging the obvious fact that a larger population set, and more stringent collection parameters, will need to be investigated in the future.
    Matrix Biology 09/2014; 40. DOI:10.1016/j.matbio.2014.08.016 · 5.07 Impact Factor
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    • "Due to their roles in carcinogenesis, [30], [35]–[41] Sulfs represent attractive therapeutic target for cancer treatment. [38], [42] "
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    ABSTRACT: Sulfs are extracellular endosulfatases that selectively remove the 6-O-sulfate groups from cell surface heparan sulfate (HS) chain. By altering the sulfation at these particular sites, Sulfs function to remodel HS chains. As a result of the remodeling activity, HSulf2 regulates a multitude of cell-signaling events that depend on interactions between proteins and HS. Previous efforts to characterize the substrate specificity of human Sulfs (HSulfs) focused on the analysis of HS disaccharides and synthetic repeating units. In this study, we characterized the substrate preferences of human HSulf2 using HS oligosaccharides with various lengths and sulfation degrees from several naturally occurring HS sources by applying liquid chromatography mass spectrometry based glycomics methods. The results showed that HSulf2 preferentially digests highly sulfated HS oligosaccharides with zero acetyl groups and this preference is length dependent. In terms of length of oligosaccharides, HSulf2 digestion induced more sulfation decrease on DP6 (DP: degree of polymerization) compared to DP2, DP4 and DP8. In addition, the HSulf2 preferentially digests the oligosaccharide domain located at the non-reducing end (NRE) of the HS and heparin chain. In addition, the HSulf2 digestion products were altered only for specific isomers. HSulf2 treated NRE oligosaccharides also showed greater decrease in cell proliferation than those from internal domains of the HS chain. After further chromatographic separation, we identified the three most preferred unsaturated hexasaccharide for HSulf2.
    PLoS ONE 08/2014; 9(8):e105143. DOI:10.1371/journal.pone.0105143 · 3.23 Impact Factor
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    • "Recently, a direct involvement of individual HS-metabolic enzymes in carcinogenesis was demonstrated, although for some enzymes the obtained data are still controversial. Potential tumor-suppressor function is shown for EXT1, NDST4, GLCE, and SULF1 genes and changes of their expression were detected in different human tumors: EXT1 is epigenetically inactivated in leukemia and non-melanoma skin human primary tumors and cell lines (16) and mutationally inactivated in solid osteochondromas (17), but EXT1 expression is associated with bad prognosis in multiple myeloma cells (18); NDST4 is a novel candidate tumor-suppressor gene, and the loss of its function might be involved in colorectal cancer progression (19); GLCE is down-regulated in both breast primary tumors and cell lines (20, 21) and lung cancer cell lines (22), although GLCE up-regulation correlates with aggressive disease in prostate cancer (23, 24); SULF1 is epigenetically silenced in ovarian cancer cell lines and primary tumors (25); in contrast to the tumor-suppressor effect of SULF1, SULF2 expression promotes hepatocellular carcinoma cell growth in vitro and in vivo (26); SULF2 is up-regulated in NSCLC and other cancers and implicated as a driver of carcinogenesis in NSCLC, pancreatic cancer, and hepatocellular carcinoma (27); enhanced heparanase-1 expression correlates with poor prognosis in most of the cancers in which it has been examined, and over-expression and knockout studies clearly implicate the heparanase as a master regulator of cancer progression and metastasis (28, 29). All the results support an involvement of HS-metabolic enzymes in carcinogenesis and show complex changes of their expression levels in tumors. "
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    ABSTRACT: Heparan sulfates (HSs) are key components of mammalian cells surface and extracellular matrix. Structure and composition of HS, generated by HS-biosynthetic system through non-template-driven process, are significantly altered in cancer tissues. The aim of this study was to investigate the involvement of HS-metabolic machinery in prostate carcinogenesis. Transcriptional patterns of HS-metabolic enzymes (EXT1, EXT2, NDST1, NDST2, GLCE, 3OST1/HS3ST1, SULF1, SULF2, HPSE) were determined in normal, benign, and cancer human prostate tissues and cell lines (PNT2, LNCaP, PC3, DU145). Stability of the HS-metabolic system patterns under the pressure of external or internal stimuli was studied. Overall impairment of transcriptional activity of HS-metabolic machinery was detected in benign prostate hyperplasia, while both significant decrease in the transcriptional activity and changes in the expression patterns of HS metabolism-involved genes were observed in prostate tumors. Prostate cancer cell lines possessed specific transcriptional patterns of HS metabolism-involved genes; however, expression activity of the system was similar to that of normal prostate PNT2 cells. HS-metabolic system was able to dynamically react to different external or internal stimuli in a cell type-dependent manner. LNCaP cells were sensitive to the external stimuli (5-aza-deoxycytidin or Trichostatin A treatments; co-cultivation with human fibroblasts), whereas PC3 cells almost did not respond to the treatments. Ectopic GLCE over-expression resulted in transcriptional activation of HS-biosynthetic machinery in both cell lines, suggesting an existence of a self-regulating mechanism for the coordinated transcription of HS metabolism-involved genes. Taken together, these findings demonstrate impairment of HS-metabolic system in prostate tumors in vivo but not in prostate cancer cells in vitro, and suggest that as a potential microenvironmental biomarker for prostate cancer diagnostics and treatment.
    Frontiers in Oncology 04/2014; 4:79. DOI:10.3389/fonc.2014.00079
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