| Written | 2013-04 | Lewis Roberts, Chunling Hu |
| Division of Gastroenterology, Hepatology, Mayo Clinic, Mayo Clinic Cancer Center, Rochester, MN 55905, USA |
| Identity |
| Alias_symbol (synonym) | KIAA1247 |
| HSULF-2 | |
| SULF-2 | |
| Other alias | |
| HGNC (Hugo) | SULF2 |
| LocusID (NCBI) | 55959 |
| Atlas_Id | 43735 |
| Location | 20q13.12 [Link to chromosome band 20q13] |
| Location_base_pair | Starts at 47657406 and ends at 47786616 bp from pter ( according to hg19-Feb_2009) [Mapping SULF2.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| ARFGEF2 (20q13.13) / SULF2 (20q13.12) | DDX21 (10q22.1) / SULF2 (20q13.12) | SULF2 (20q13.12) / PRICKLE2 (3p14.1) | |
| SULF2 (20q13.12) / ZNF217 (20q13.2) | UBE2V1 (20q13.13) / SULF2 (20q13.12) | ZMYND8 (20q13.12) / SULF2 (20q13.12) | |
| 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). |
| Protein |
 | |
| 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 |
| Note | |
| Entity | 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 | 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 | 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. |
| Bibliography |
| SULFs in human neoplasia: implication as progression and prognosis factors. |
| Bret C, Moreaux J, Schved JF, Hose D, Klein B. |
| J Transl Med. 2011 May 21;9:72. doi: 10.1186/1479-5876-9-72. |
| PMID 21599997 |
| Identification of SULF2 as a novel transcriptional target of p53 by use of integrated genomic analyses. |
| Chau BN, Diaz RL, Saunders MA, Cheng C, Chang AN, Warrener P, Bradshaw J, Linsley PS, Cleary MA. |
| Cancer Res. 2009 Feb 15;69(4):1368-74. doi: 10.1158/0008-5472.CAN-08-2742. Epub 2009 Feb 3. |
| PMID 19190338 |
| HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. |
| Dai Y, Yang Y, MacLeod V, Yue X, Rapraeger AC, Shriver Z, Venkataraman G, Sasisekharan R, Sanderson RD. |
| J Biol Chem. 2005 Dec 2;280(48):40066-73. Epub 2005 Sep 27. |
| PMID 16192265 |
| Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications. |
| Gill RB, Day A, Barstow A, Liu H, Zaman G, Dhoot GK. |
| Biochem Biophys Res Commun. 2011 Oct 28;414(3):468-73. doi: 10.1016/j.bbrc.2011.09.088. Epub 2011 Sep 24. |
| PMID 21968018 |
| The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. |
| Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, Nakamura I, Han T, Aderca I, Isomoto H, Garrity-Park MM, Shire AM, Li J, Sanderson SO, Adjei AA, Fernandez-Zapico ME, Roberts LR. |
| Hepatology. 2010a Nov;52(5):1680-9. doi: 10.1002/hep.23848. |
| PMID 20725905 |
| Sulfatase 2 protects hepatocellular carcinoma cells against apoptosis induced by the PI3K inhibitor LY294002 and ERK and JNK kinase inhibitors. |
| Lai JP, Sandhu DS, Yu C, Moser CD, Hu C, Shire AM, Aderca I, Murphy LM, Adjei AA, Sanderson S, Roberts LR. |
| Liver Int. 2010b Nov;30(10):1522-8. doi: 10.1111/j.1478-3231.2010.02336.x. Epub 2010 Sep 8. |
| PMID 21040406 |
| Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets. |
| Lai JP, Thompson JR, Sandhu DS, Roberts LR. |
| Future Oncol. 2008b Dec;4(6):803-14. doi: 10.2217/14796694.4.6.803. (REVIEW) |
| PMID 19086847 |
| Sulf loss influences N-, 2-O-, and 6-O-sulfation of multiple heparan sulfate proteoglycans and modulates fibroblast growth factor signaling. |
| Lamanna WC, Frese MA, Balleininger M, Dierks T. |
| J Biol Chem. 2008 Oct 10;283(41):27724-35. doi: 10.1074/jbc.M802130200. Epub 2008 Aug 6. |
| PMID 18687675 |
| Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis. |
| Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD. |
| Oncogene. 2010 Feb 4;29(5):635-46. doi: 10.1038/onc.2009.365. Epub 2009 Oct 26. |
| PMID 19855436 |
| Sulf-2, a proangiogenic heparan sulfate endosulfatase, is upregulated in breast cancer. |
| Morimoto-Tomita M, Uchimura K, Bistrup A, Lum DH, Egeblad M, Boudreau N, Werb Z, Rosen SD. |
| Neoplasia. 2005 Nov;7(11):1001-10. |
| PMID 16331886 |
| Expression of novel extracellular sulfatases Sulf-1 and Sulf-2 in normal and osteoarthritic articular cartilage. |
| Otsuki S, Taniguchi N, Grogan SP, D'Lima D, Kinoshita M, Lotz M. |
| Arthritis Res Ther. 2008;10(3):R61. doi: 10.1186/ar2432. Epub 2008 May 28. |
| PMID 18507859 |
| Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts. |
| Peterson SM, Iskenderian A, Cook L, Romashko A, Tobin K, Jones M, Norton A, Gomez-Yafal A, Heartlein MW, Concino MF, Liaw L, Martini PG. |
| BMC Cancer. 2010 Aug 13;10:427. doi: 10.1186/1471-2407-10-427. |
| PMID 20707913 |
| Heparan sulfate sulfatase SULF2 regulates PDGFRa signaling and growth in human and mouse malignant glioma. |
| Phillips JJ, Huillard E, Robinson AE, Ward A, Lum DH, Polley MY, Rosen SD, Rowitch DH, Werb Z. |
| J Clin Invest. 2012 Mar 1;122(3):911-22. doi: 10.1172/JCI58215. Epub 2012 Feb 1. |
| PMID 22293178 |
| Glycomics analysis of mammalian heparan sulfates modified by the human extracellular sulfatase HSulf2. |
| Staples GO, Shi X, Zaia J. |
| PLoS One. 2011 Feb 8;6(2):e16689. doi: 10.1371/journal.pone.0016689. |
| PMID 21347431 |
| Functional consequences of the subdomain organization of the sulfs. |
| Tang R, Rosen SD. |
| J Biol Chem. 2009 Aug 7;284(32):21505-14. doi: 10.1074/jbc.M109.028472. Epub 2009 Jun 11. |
| PMID 19520866 |
| 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, Morimoto-Tomita M, Bistrup A, Li J, Lyon M, Gallagher J, Werb Z, Rosen SD. |
| BMC Biochem. 2006 Jan 17;7:2. |
| PMID 16417632 |
| Sulfatase 1 and sulfatase 2 in hepatocellular carcinoma: associated signaling pathways, tumor phenotypes, and survival. |
| Yang JD, Sun Z, Hu C, Lai J, Dove R, Nakamura I, Lee JS, Thorgeirsson SS, Kang KJ, Chu IS, Roberts LR. |
| Genes Chromosomes Cancer. 2011 Feb;50(2):122-35. doi: 10.1002/gcc.20838. |
| PMID 21104785 |
| Citation |
| This paper should be referenced as such : |
| Roberts, L ; Hu, C |
| SULF2 (sulfatase 2) |
| Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):713-715. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/SULF2ID43735ch20q13.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ] |
|
t(3;20)(p14;q13) SULF2/PRICKLE2
ARFGEF2/SULF2 (20q13) SULF2/ZNF217 (20q13) UBE2V1/SULF2 (20q13) ZMYND8/SULF2 (20q13) |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu May 21 19:49:19 CEST 2020 |
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