Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJCNCO0)

• DOT Name: Extracellular sulfatase Sulf-1 (SULF1)
• Synonyms: hSulf-1; Arylsulfatase; EC 3.1.6.1; N-acetylglucosamine-6-sulfatase; EC 3.1.6.14
• Gene Name: SULF1
• Related Disease:
  Bladder transitional cell carcinoma
  Colon adenoma
  Gastric neoplasm
  Lung adenocarcinoma
  T lymphoblastic leukaemia
  Testicular cancer
  Transitional cell carcinoma
  Urothelial carcinoma
  Adult hepatocellular carcinoma
  Benign prostatic hyperplasia
  Brain cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colonic neoplasm
  Colorectal carcinoma
  Epithelial ovarian cancer
  Fatty liver disease
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Intervertebral disc degeneration
  Liver cancer
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic tumour
  Pancreatitis
  Pneumonia
  Pneumonitis
  Precancerous condition
  Pulmonary fibrosis
  Ductal breast carcinoma in situ
  Knee osteoarthritis
  Carcinoma of liver and intrahepatic biliary tract
  Melanoma
  Pancreatic cancer
• UniProt ID: SULF1_HUMAN
• EC Number: 3.1.6.1; 3.1.6.14
• Pfam ID: PF12548 ; PF00884
• Sequence:
  MKYSCCALVLAVLGTELLGSLCSTVRSPRFRGRIQQERKNIRPNIILVLTDDQDVELGSL
  QVMNKTRKIMEHGGATFINAFVTTPMCCPSRSSMLTGKYVHNHNVYTNNENCSSPSWQAM
  HEPRTFAVYLNNTGYRTAFFGKYLNEYNGSYIPPGWREWLGLIKNSRFYNYTVCRNGIKE
  KHGFDYAKDYFTDLITNESINYFKMSKRMYPHRPVMMVISHAAPHGPEDSAPQFSKLYPN
  ASQHITPSYNYAPNMDKHWIMQYTGPMLPIHMEFTNILQRKRLQTLMSVDDSVERLYNML
  VETGELENTYIIYTADHGYHIGQFGLVKGKSMPYDFDIRVPFFIRGPSVEPGSIVPQIVL
  NIDLAPTILDIAGLDTPPDVDGKSVLKLLDPEKPGNRFRTNKKAKIWRDTFLVERGKFLR
  KKEESSKNIQQSNHLPKYERVKELCQQARYQTACEQPGQKWQCIEDTSGKLRIHKCKGPS
  DLLTVRQSTRNLYARGFHDKDKECSCRESGYRASRSQRKSQRQFLRNQGTPKYKPRFVHT
  RQTRSLSVEFEGEIYDINLEEEEELQVLQPRNIAKRHDEGHKGPRDLQASSGGNRGRMLA
  DSSNAVGPPTTVRVTHKCFILPNDSIHCERELYQSARAWKDHKAYIDKEIEALQDKIKNL
  REVRGHLKRRKPEECSCSKQSYYNKEKGVKKQEKLKSHLHPFKEAAQEVDSKLQLFKENN
  RRRKKERKEKRRQRKGEECSLPGLTCFTHDNNHWQTAPFWNLGSFCACTSSNNNTYWCLR
  TVNETHNFLFCEFATGFLEYFDMNTDPYQLTNTVHTVERGILNQLHVQLMELRSCQGYKQ
  CNPRPKNLDVGNKDGGSYDLHRGQLWDGWEG
• Function: Exhibits arylsulfatase activity and highly specific endoglucosamine-6-sulfatase activity. It can remove sulfate from the C-6 position of glucosamine within specific subregions of intact heparin. Diminishes HSPG (heparan sulfate proteoglycans) sulfation, inhibits signaling by heparin-dependent growth factors, diminishes proliferation, and facilitates apoptosis in response to exogenous stimulation.
• Tissue Specificity: 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. Down-regulation seen in ovarian carcinoma cell lines, ovarian cancers, breast, pancreatic, renal and hepatocellular carcinoma cell lines.

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Colon adenoma	DISPMZ3U	Definitive	Altered Expression	[2]
Gastric neoplasm	DISOKN4Y	Definitive	Posttranslational Modification	[3]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
T lymphoblastic leukaemia	DIS2PNPP	Definitive	Altered Expression	[2]
Testicular cancer	DIS6HNYO	Definitive	Altered Expression	[2]
Transitional cell carcinoma	DISWVVDR	Definitive	Biomarker	[1]
Urothelial carcinoma	DISRTNTN	Definitive	Biomarker	[1]
Adult hepatocellular carcinoma	DIS6ZPAI	Strong	Posttranslational Modification	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Brain cancer	DISBKFB7	Strong	Altered Expression	[6]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[11]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[14]
Liver cancer	DISDE4BI	Strong	Biomarker	[13]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[15]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[15]
Lung neoplasm	DISVARNB	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[17]
Osteoarthritis	DIS05URM	Strong	Biomarker	[18]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[12]
Pancreatitis	DIS0IJEF	Strong	Genetic Variation	[19]
Pneumonia	DIS8EF3M	Strong	Biomarker	[20]
Pneumonitis	DIS88E0K	Strong	Biomarker	[20]
Precancerous condition	DISV06FL	Strong	Biomarker	[21]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[22]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[23]
Knee osteoarthritis	DISLSNBJ	moderate	Biomarker	[18]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[13]
Melanoma	DIS1RRCY	Limited	Altered Expression	[24]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Extracellular sulfatase Sulf-1 (SULF1) increases the response to substance of Cisplatin.	[46]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[31]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[32]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[33]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[34]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[35]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[37]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[43]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[44]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Extracellular sulfatase Sulf-1 (SULF1).	[45]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Extracellular sulfatase Sulf-1 (SULF1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Extracellular sulfatase Sulf-1 (SULF1).	[39]

References

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• [3] Promoter hypermethylation correlates with the Hsulf-1 silencing in human breast and gastric cancer.Int J Cancer. 2009 Feb 1;124(3):739-44. doi: 10.1002/ijc.23960.
• [4] hSulf-1 gene exhibits anticancer efficacy through negatively regulating VEGFR-2 signaling in human cancers.PLoS One. 2011;6(8):e23274. doi: 10.1371/journal.pone.0023274. Epub 2011 Aug 10.
• [5] Distinctive gene expression of prostatic stromal cells cultured from diseased versus normal tissues.J Cell Physiol. 2007 Jan;210(1):111-21. doi: 10.1002/jcp.20828.
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• [12] Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer.Mol Cancer. 2005 Apr 7;4(1):14. doi: 10.1186/1476-4598-4-14.
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• [18] Suppression of cartilage degeneration by intra-articular injection of heparan sulfate 6-O endosulfatase in a mouse osteoarthritis model.Histol Histopathol. 2017 Jul;32(7):725-733. doi: 10.14670/HH-11-838. Epub 2016 Nov 3.
• [19] SULF1/SULF2 splice variants differentially regulate pancreatic tumour growth progression.Exp Cell Res. 2014 Jun 10;324(2):157-71. doi: 10.1016/j.yexcr.2014.04.001. Epub 2014 Apr 12.
• [20] Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses.Am J Physiol Lung Cell Mol Physiol. 2019 Nov 1;317(5):L667-L677. doi: 10.1152/ajplung.00175.2019. Epub 2019 Aug 28.
• [21] Genetic variations in the SULF1 gene alter the risk of cervical cancer and precancerous lesions.Oncol Lett. 2018 Sep;16(3):3833-3841. doi: 10.3892/ol.2018.9104. Epub 2018 Jul 6.
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• [23] Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma.Breast Cancer Res. 2008;10(5):R87. doi: 10.1186/bcr2157. Epub 2008 Oct 17.
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• [29] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
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• [32] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [33] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [34] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [35] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [36] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [37] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [38] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
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• [42] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [43] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [44] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [45] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
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