SULF1 (sulfatase 1)

2012-03-01   Jérôme Moreaux 

INSERM U1040, institut de recherche en biotherapie, CHRU Saint Eloi, 80 Av Augustain Fliche, 34295 Montpellier CEDEX 5, France

Identity

HGNC
LOCATION
8q13.2
LOCUSID
ALIAS
SULF-1
FUSION GENES

DNA/RNA

Note

The sulfation pattern of heparan sulfate chains influences signaling events mediated by heparan sulfate proteoglycans located on cell surface. SULF1 is an endosulfatase able to cleave specific 6-O sulfate groups within the heparan chains. This action can modulate signaling processes, modulating the effects of heparan sulfate by altering binding sites for signaling molecules.
Atlas Image
Adapted from Genecards.

Description

Size: 5551 bp.

Transcription

4 isoforms:
- Homo sapiens sulfatase 1 (SULF1), transcript variant 1, mRNA, 5716 bp
Accession: NM_001128205.1 GI: 189571640
- Homo sapiens sulfatase 1 (SULF1), transcript variant 2, mRNA, 5554 bp
Accession: NM_001128206.1 GI: 189571642
- Homo sapiens sulfatase 1 (SULF1), transcript variant 3, mRNA, 5710 bp
Accession: NM_015170.2 GI: 189571635
- Homo sapiens sulfatase 1 (SULF1), transcript variant 4, mRNA, 5548 bp
Accession: NM_001128204.1 GI: 189571637

Proteins

Note

Sulfs are sulfatases that edit the sulfation status of heparan sulfate proteoglycans on the outside of cells and regulate a number of critical signaling pathways. The Sulfs are dysregulated in many cancers. The Sulfs are synthesized as pre-proproteins. The signal sequence is removed and the pro-protein is cleaved by a furin-type proteinase. Sulfs mature proteins are secreted as well as retained on the cell surface.

Description

871 amino acids; 101027 Da.

Expression

Expressed at highest levels in testis, stomach, skeletal muscle, lung, kidney, pancreas, small intestine and colon. It is also detected in normal ovarian surface epithelial cells.

Localisation

Sulfs mature proteins are secreted as well as retained on the cell surface.

Function

The Sulfs are endoglucosamine-6-sulfatases. They liberate 6-O-S mainly from trisulfated disaccharide units within the S-domains of heparin/HS chains. The Sulfs have been shown to modulate the interaction of a number of protein ligands with heparin or heparan sulfate.

Homology

SULF1 shares about 64% identity with SULF2.

Implicated in

Entity name
Ovarian cancer
Oncogenesis
Sulf1 expression was found to be absent or significantly downregulated in ovarian cancer resulting in highly sulfated heparin sulfate proteoglycans. It has been observed that this down-regulation results in increased sulfation of heparin sulfate chains and could produce the stabilization of ternary receptor complexes, leading to an increased in GF signaling, as described for heparin-binding epidermal growth factor-like growth factor (HB-EGF), fibroblast growth factor 2 (FGF2) or amphiregulin in ovarian cancer. This modulation of GF effects can affect major events including proliferation of tumor cells. Epigenetic silencing by methylation is associated with ovarian cancer cells and primary ovarian cancer tissues lacking Sulf1 expression. Cisplatin-induced apoptosis of the ovarian cancer cell line, OV207, requires Sulf1 activity.
Entity name
Breast cancer
Oncogenesis
Sulf1 expression was first described to be significantly downregulated in breast cancer. Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in breast cancer compared to normal counterpart. It has been observed that this down-regulation results in increased sulfation of heparin sulfate chains and could produce the stabilization of ternary receptor complexes, leading to an increased in growth factors signaling, as described for heparin-binding epidermal growth factor-like growth factor (HB-EGF), fibroblast growth factor 2 (FGF2) or amphiregulin in breast cancer. This modulation of GF effects can affect major events including proliferation of tumor cells. A marked reduction of the growth of myeloma or breast cancer cell lines was observed in severe combined immunodeficient mice when injected cell lines were transfected with SULF1 cDNA. It was found an aberrant hypermethylation of the Sulf1 promoter in breast cancer cell lines and patient samples, leading to a reduction of Sulf1 expression.
Entity name
Hepatocellular carcinoma
Oncogenesis
Sulf1 expression was also found to be significantly downregulated in hepatocellular carcinoma. It has also been observed that this down-regulation results in increased sulfation of heparin sulfate chains and could produce the stabilization of ternary receptor complexes, leading to an increased in growth factors signaling. Forced expression of SULF1 also significantly delayed the growth of hepatocellular carcinoma cell lines xenografts in nude mice. Sulf1 enhances acetylation of histone H4 by inhibiting HDAC, which subsequently decreased hepatocellular carcinoma cell tumorogenesis in mouse model.
Entity name
Pancreatic cancer
Oncogenesis
Hsulf-1-mediated desulphation of HSPGs reduces the growth ability of pancreatic cancer cells, but increases the basal invasiveness of these cells and chemoresistance, suggesting an important role of this enzyme in pancreatic cancer progression. Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in pancreatic adenocarinoma compared to normal counterpart.
Entity name
Head and neck squamous cell carcinoma
Oncogenesis
Sulf1 expression was also found to be significantly downregulated in head and neck squamous cell carcinoma cell lines. It has also been observed that this down-regulation results in increased sulfation of heparin sulfate chains and could produce the stabilization of ternary receptor complexes, leading to an increased in growth factors signaling in head and neck squamous cell carcinoma cell lines. Hepatocyte growth factor (HGF)-mediated motility and invasion were attenuated in neck squamous cell carcinoma cell lines displaying an overexpression of this sulfatase. However, recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in head and neck squamous cell carcinoma compared to normal counterpart.
Entity name
Leukemia
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in leukemia compared to normal counterpart.
Entity name
Gastric cancer
Oncogenesis
Promoter hypermethylation is correlated with the HSulf-1 silencing in gastric cancer. The restoration of the expression of HSulf-1 inhibited cell proliferation, motility, and invasion of the MKN28 cell line in vitro, as well as in a xenograft mouse model. No noticeable changes in proliferation and motility were observed following restoration of HSulf-1 in another gastric cancer cell line AGS. HSulf-1 function as a negative regulator of proliferation and invasion in MKN28 gastric cancer cell line by suppressing Wnt/β-catenin signaling. However, as for others cancers, recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in leukemia compared to normal counterpart.
Entity name
Colon cancer
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in colon cancer compared to normal counterpart.
Entity name
Adrenal cancer
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in adrenal cancer compared to normal counterpart.
Entity name
Esophageal cancer
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in esophageal cancer compared to normal counterpart.
Entity name
Lung cancer
Prognosis
In a cohort of 127 patients with lung adenocarcinoma, it was described that high expression of Sulf1 is associated with a bad prognosis compared to patients with low Sulf1 expression.
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in esophageal cancer compared to normal counterpart.
Entity name
Mesothelioma
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in mesothelioma compared to normal counterpart. Furthermore, a review of transcriptome studies identified Sulf1 as a mesothelioma gene that could represent a new biomarker or therapeutic target in mesothelioma.
Entity name
Renal carcinoma
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in renal carcinoma compared to normal counterpart.
Entity name
Sarcoma
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in sarcoma compared to normal counterpart.
Entity name
Melanoma
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in cutaneous melanoma compared to normal skin.
Entity name
Testicular cancer
Oncogenesis
Recent analysis using microarray data demonstrated a significant upregulation of Sulf1 in testicular cancer compared to normal counterpart.

Bibliography

Pubmed IDLast YearTitleAuthors
166036502006Hsulf-1 regulates growth and invasion of pancreatic cancer cells.Abiatari I et al
215999972011SULFs in human neoplasia: implication as progression and prognosis factors.Bret C et al
190060692009Promoter hypermethylation correlates with the Hsulf-1 silencing in human breast and gastric cancer.Chen Z et al
120003112002Fibroblast growth factor-2 binds to small heparin-derived oligosaccharides and stimulates a sustained phosphorylation of p42/44 mitogen-activated protein kinase and proliferation of rat mammary fibroblasts.Delehedde M et al
114792332001Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma.Dong G et al
90656491997Detection of MET oncogene/hepatocyte growth factor receptor in lymph node metastases from head and neck squamous cell carcinomas.Galeazzi E et al
126865632003Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer.Lai J et al
149735532004HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma.Lai JP et al
167626342006SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma.Lai JP et al
158171232005Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer.Li J et al
108165962000Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis.Lundin L et al
221982102012A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma.Melaiu O et al
173633712007Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer.Narita K et al
167781742006HSulf-1 inhibits angiogenesis and tumorigenesis in vivo.Narita K et al
206296192010Sulf-2: an extracellular modulator of cell signaling and a cancer target candidate.Rosen SD et al
173109982007Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance.Staub J et al

Other Information

Locus ID:

NCBI: 23213
MIM: 610012
HGNC: 20391
Ensembl: ENSG00000137573

Variants:

dbSNP: 23213
ClinVar: 23213
TCGA: ENSG00000137573
COSMIC: SULF1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000137573ENST00000260128Q8IWU6
ENSG00000137573ENST00000260128A0A024R809
ENSG00000137573ENST00000402687Q8IWU6
ENSG00000137573ENST00000402687A0A024R809
ENSG00000137573ENST00000419716Q8IWU6
ENSG00000137573ENST00000419716A0A024R809
ENSG00000137573ENST00000458141Q8IWU6
ENSG00000137573ENST00000458141A0A024R809
ENSG00000137573ENST00000525061E9PI06
ENSG00000137573ENST00000525999E9PJL8
ENSG00000137573ENST00000528783E9PPQ3
ENSG00000137573ENST00000529134E9PS14
ENSG00000137573ENST00000531512H0YDR1
ENSG00000137573ENST00000534179E9PLS5
ENSG00000137573ENST00000616868A0A087WWR8

Expression (GTEx)

0
50
100
150
200

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
123682952002Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans.134
126865632003Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer.95
161922652005HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.65
161922652005HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.65
146995032004hSulf1 Sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling.62
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
186876752008Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.58
236845512013MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways.55
158171232005Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer.43
173633712007Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer.38

Citation

Jérôme Moreaux

SULF1 (sulfatase 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-03-01

Online version: http://atlasgeneticsoncology.org/gene/44378/sulf1