SULF2 (sulfatase 2)

2013-04-01 Lewis Roberts , Chunling Hu Affiliation

Division of Gastroenterology, Hepatology, Mayo Clinic, Mayo Clinic Cancer Center, Rochester, MN 55905, USA

Identity

HGNC

SULF2

LOCATION

20q13.12

LOCUSID

55959

ALIAS

HSULF-2

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

SULF2 55959 chr 20: 46286150-46415360. The gene encompasses 130 kb of DNA; 21 exons.

Transcription

3 transcripts: transcript variant 1, 3909 bp linear mRNA, 21 exons (NM_018837); transcript variant 2, 4239 bp linear mRNA, 21 exons (NM_198596); transcript variant 3, 4248 bp linear mRNA, 21 exons (NM_001161841).

Proteins

Schematic diagram of SULF2 with domains.

Description

870 amino acid; 100 kDa protein; post translational modification: 11 N-glycosylation sites; contains from N-term to C-term, a signal peptide (1-24), a enzymatic domain (25-400) which contains a conserved cysteine (88) essential for the catalytic activity, a hydrophilic domain (401-739) which contains four lysines and arginies rich domains suited for interactions with sulfated HSGAGs that fit the heparin-binding motif, and a glucosamine-6-sulfatase domain (740-870).

Expression

Widely expressed, especially in ovary, skeletal muscle, stomach, brain, uterus, heart, kidney, and placenta.

Localisation

Extracellular space, cell surface, plasma membrane, endoplasmic reticulum, and Golgi stack.

Function

SULF2 is a member of a novel family of extracellular HS 6-O endosulfatases with heparin-degrading endosulfatase activity. SULF2 desulfates HS and increases the local concentration of growth factors in the extracellular matrix. The released growth factors then bind to their cell surface receptors, with the consequent activation of cell growth and survival pathways in HCC. SULF2 up-regulated GPC3 expression and FGF2 ligand-receptor binding and signaling. It has been shown that SULF2 liberates growth factors such as Wnt3a from HSPGs such as GPC3 on the cell surface and in the extracellular matrix by desulfating heparan sulfate (HS). It has been reported that SULF2 mRNA is up-regulated in human breast cancers, and suppression of SULF2 expression decreases tumorigenesis of pancreatic cancer cell lines. SULF2 regulates PDGFRα signaling and growth in malignant glioma.

Homology

Conserved in Rhesus monkey, dog, cow, mouse, rat, chicken, and zebrafish.

Mutations

Somatic

Identified mutations in various cancers.

Implicated in

Entity name

Hepatocellular carcinoma (HCC)

Prognosis

In a microarray experiment performed on paired benign and tumor tissues from HCC patients, SULF2 expression was higher in the tumors than in the benign tissues in 79 (57%) of 139 HCCs. Patients with tumors expressing high SULF2 levels had a significantly poorer prognosis than those with tumor expressing low SULF2 levels (Lai et al., 2008a).

Oncogenesis

Expression of SULF2 promotes HCC cell proliferation and migration. Knockdown of SULF2 decreases HCC cell proliferation and migration. SULF2 promotes tumorigenesis in nude mice and up-regulates GPC3 in vivo (Lai et al., 2008a).

Entity name

Lung cancer

Prognosis

Paired samples of lung squamous carcinoma and non malignant neighboring tissue were obtained from 10 patients undergoing surgical resection. SULF2 increased in 8/10 pairs with a mean increase of 3 ± 0.3-fold. qPCR analysis of SULF2 in archived cases of lung carcinoma verified it. SULF2 increased 4 ± 0.3 fold in squamous carcinomas and 3 ± 0.4 fold in adenocarcinomas (Lemjabbar-Alaoui et al., 2010).

Oncogenesis

Knockdown of SULF2 or expression of dominant-negative SULF2 reduces growth of lung cancer cells. SULF2 over-expression in non-malignant bronchial epithelial cells induces a transformed phenotype in culture. SULF2 knockdown reduces growth of tumors arising from lung cancer cells (Lemjabbar-Alaoui et al., 2010).

Entity name

Glioblastoma (GBM)

Prognosis

SULF2 expression is elevated in GBM. Unsing a stringent cutoff of a 10-fold increase in SULF2 SAGE tags over levels in normal brain to define high SULF2 levels, 7 of 16 GBMs has increased SULF2 expression. Strikingly, in an independent set of 424 primary human GBM tumors, SULF2 expression was increased in 46% (197/424) of tumors related to normal brain. Immunohistochemistry on an independent set of 57 primary human GBM tumors demonstrated SULF2 protein in tumor cells in 50% of tumors. SULF2 expression is associated with the proneural subtype of GBM characterized by abnormalities in the PDGFRα-signaling pathway and SULF2 expression is associated with the proneural GBM subtype (Phillips et al., 2012).

Oncogenesis

SULF2 confers a growth advantage to human GBM cells, SULF2 knockdown resulted in a significant decrease in cell viability. SULF2 also confers a growth advantage to human GBM cells in vivo. SULF2 confers increased tumorigenicity and proliferation. Prolonged survival confered by ablation of SULF2 in tumorigenic neurospheres. And absence of SULF2 resulted in decreased tumor cell proliferation in vivo (Phillips et al., 2012).

Breakpoints

Note

Fusion of ARFGEF2 exon 1 to SULF2 exons 3-21.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
21599997	2011	SULFs in human neoplasia: implication as progression and prognosis factors.	Bret C et al
19190338	2009	Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses.	Chau BN et al
16192265	2005	HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.	Dai Y et al
21968018	2011	Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications.	Gill RB et al
20725905	2010	The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation.	Lai JP et al
21040406	2010	Sulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors.	Lai JP et al
19086847	2008	Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets.	Lai JP et al
18687675	2008	Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling.	Lamanna WC et al
19855436	2010	Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.	Lemjabbar-Alaoui H et al
16331886	2005	Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer.	Morimoto-Tomita M et al
18507859	2008	Expression of novel extracellular sulfatases Sulf-1 and Sulf-2 in normal and osteoarthritic articular cartilage.	Otsuki S et al
20707913	2010	Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts.	Peterson SM et al
22293178	2012	Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma.	Phillips JJ et al
21347431	2011	Glycomics analysis of mammalian heparan sulfates modified by the human extracellular sulfatase HSulf2.	Staples GO et al
19520866	2009	Functional consequences of the subdomain organization of the sulfs.	Tang R et al
16417632	2006	HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1.	Uchimura K et al
21104785	2011	Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival.	Yang JD et al

Other Information

Locus ID:

NCBI: 55959
MIM: 610013
HGNC: 20392
Ensembl: ENSG00000196562

Variants:

dbSNP: 55959
ClinVar: 55959
TCGA: ENSG00000196562
COSMIC: SULF2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000196562	ENST00000359930	Q8IWU5
ENSG00000196562	ENST00000437955	B1AMP9
ENSG00000196562	ENST00000467815	Q8IWU5
ENSG00000196562	ENST00000484875	Q8IWU5
ENSG00000196562	ENST00000495544	H0Y872

Expression (GTEx)

100

150

200

250

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
35472437	2022	SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer.	9
36068294	2022	Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts.	8
35472437	2022	SULF2 enhances GDF15-SMAD axis to facilitate the initiation and progression of pancreatic cancer.	9
36068294	2022	Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts.	8
33735525	2021	Sulfatase 2 (SULF2) Monoclonal Antibody 5D5 Suppresses Human Cholangiocarcinoma Xenograft Growth Through Regulation of a SULF2-Platelet-Derived Growth Factor Receptor Beta-Yes-Associated Protein Signaling Axis.	8
33908819	2021	Extracellular sulfatases as potential blood-based biomarkers for early detection of lung cancer.	1
33735525	2021	Sulfatase 2 (SULF2) Monoclonal Antibody 5D5 Suppresses Human Cholangiocarcinoma Xenograft Growth Through Regulation of a SULF2-Platelet-Derived Growth Factor Receptor Beta-Yes-Associated Protein Signaling Axis.	8
33908819	2021	Extracellular sulfatases as potential blood-based biomarkers for early detection of lung cancer.	1
30698737	2019	TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment.	27
31499680	2019	MicroRNA-527 inhibits TGF-β/SMAD induced epithelial-mesenchymal transition via downregulating SULF2 expression in non-small-cell lung cancer.	9
30698737	2019	TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment.	27
31499680	2019	MicroRNA-527 inhibits TGF-β/SMAD induced epithelial-mesenchymal transition via downregulating SULF2 expression in non-small-cell lung cancer.	9
29360432	2018	Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events.	4
29720727	2018	Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer.	11
29360432	2018	Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events.	4

Citation

Lewis Roberts ; Chunling Hu

SULF2 (sulfatase 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-04-01

Online version: http://atlasgeneticsoncology.org/gene/43735/gene-explorer/tumors-explorer/cancer-prone-explorer/