Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2SJN0X)

• DOT Name: Hyaluronidase-1 (HYAL1)
• Synonyms: Hyal-1; EC 3.2.1.35; Hyaluronoglucosaminidase-1; Lung carcinoma protein 1; LuCa-1
• Gene Name: HYAL1
• Related Disease:
  Mucopolysaccharidosis type 9
  Small-cell lung cancer
  Bladder cancer
  Breast carcinoma
  Carcinoma
  Endometrial carcinoma
  Head-neck squamous cell carcinoma
  Juvenile idiopathic arthritis
  Lung neoplasm
  Metastatic prostate carcinoma
  Morquio syndrome
  Mucopolysaccharidosis
  Nasal polyp
  Neoplasm
  Osteoarthritis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Pulmonary hypertension
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Colorectal carcinoma
  Pancreatic cancer
  Chronic obstructive pulmonary disease
  Epithelial ovarian cancer
  Glioma
  Lysosomal storage disease
  Non-small-cell lung cancer
• UniProt ID: HYAL1_HUMAN
• PDB ID: 2PE4
• EC Number: 3.2.1.35
• Pfam ID: PF01630
• Sequence:
  MAAHLLPICALFLTLLDMAQGFRGPLLPNRPFTTVWNANTQWCLERHGVDVDVSVFDVVA
  NPGQTFRGPDMTIFYSSQLGTYPYYTPTGEPVFGGLPQNASLIAHLARTFQDILAAIPAP
  DFSGLAVIDWEAWRPRWAFNWDTKDIYRQRSRALVQAQHPDWPAPQVEAVAQDQFQGAAR
  AWMAGTLQLGRALRPRGLWGFYGFPDCYNYDFLSPNYTGQCPSGIRAQNDQLGWLWGQSR
  ALYPSIYMPAVLEGTGKSQMYVQHRVAEAFRVAVAAGDPNLPVLPYVQIFYDTTNHFLPL
  DELEHSLGESAAQGAAGVVLWVSWENTRTKESCQAIKEYMDTTLGPFILNVTSGALLCSQ
  ALCSGHGRCVRRTSHPKALLLLNPASFSIQLTPGGGPLSLRGALSLEDQAQMAVEFKCRC
  YPGWQAPWCERKSMW
• Function: May have a role in promoting tumor progression. May block the TGFB1-enhanced cell growth.
• Tissue Specificity: Highly expressed in the liver, kidney and heart. Weakly expressed in lung, placenta and skeletal muscle. No expression detected in adult brain. Isoform 1 is expressed only in bladder and prostate cancer cells, G2/G3 bladder tumor tissues and lymph node specimens showing tumor invasive tumors cells. Isoform 3, isoform 4, isoform 5 and isoform 6 are expressed in normal bladder and bladder tumor tissues.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Hyaluronan uptake and degradation (R-HSA-2160916)
  MPS IX - Natowicz syndrome (R-HSA-2206280)
  CS/DS degradation (R-HSA-2024101)
• BioCyc Pathway: MetaCyc:HS03763-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mucopolysaccharidosis type 9	DISFSB6J	Definitive	Autosomal recessive	[1]
Small-cell lung cancer	DISK3LZD	Definitive	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[7]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[10]
Morquio syndrome	DIS2Y2P2	Strong	Altered Expression	[11]
Mucopolysaccharidosis	DISB083T	Strong	Biomarker	[12]
Nasal polyp	DISLP3XE	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[14]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[16]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[17]
Pancreatic cancer	DISJC981	moderate	Biomarker	[18]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Altered Expression	[19]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[20]
Glioma	DIS5RPEH	Limited	Altered Expression	[2]
Lysosomal storage disease	DIS6QM6U	Limited	Genetic Variation	[21]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dactinomycin	DM2YGNW	Approved	Hyaluronidase-1 (HYAL1) increases the Cell-mediated cytotoxicity ADR of Dactinomycin.	[38]

14 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 Hyaluronidase-1 (HYAL1).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hyaluronidase-1 (HYAL1).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hyaluronidase-1 (HYAL1).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hyaluronidase-1 (HYAL1).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hyaluronidase-1 (HYAL1).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Hyaluronidase-1 (HYAL1).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Hyaluronidase-1 (HYAL1).	[28]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Hyaluronidase-1 (HYAL1).	[30]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Hyaluronidase-1 (HYAL1).	[31]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hyaluronidase-1 (HYAL1).	[32]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Hyaluronidase-1 (HYAL1).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hyaluronidase-1 (HYAL1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Hyaluronidase-1 (HYAL1).	[36]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Hyaluronidase-1 (HYAL1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Hyaluronidase-1 (HYAL1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hyaluronidase-1 (HYAL1).	[34]

References

• [1] Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med. 1996 Oct 3;335(14):1029-33. doi: 10.1056/NEJM199610033351405.
• [2] Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines.Oncol Rep. 2003 May-Jun;10(3):609-16.
• [3] Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer.Oncotarget. 2017 Apr 11;8(15):24262-24274. doi: 10.18632/oncotarget.10529.
• [4] Role of HYAL1 expression in primary breast cancer in the formation of brain metastases.Breast Cancer Res Treat. 2017 Apr;162(3):427-438. doi: 10.1007/s10549-017-4135-6. Epub 2017 Feb 6.
• [5] Hyaluronan synthase and hyaluronidase expression in serous ovarian carcinoma is related to anatomic site and chemotherapy exposure.Int J Mol Sci. 2012 Oct 10;13(10):12925-38. doi: 10.3390/ijms131012925.
• [6] Expression patterns of hyaluronan, hyaluronan synthases and hyaluronidases indicate a role for hyaluronan in the progression of endometrial cancer.Gynecol Oncol. 2005 Aug;98(2):193-202. doi: 10.1016/j.ygyno.2005.02.031.
• [7] Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors.Int J Cancer. 2003 Sep 1;106(3):438-45. doi: 10.1002/ijc.11252.
• [8] A complete deficiency of Hyaluronoglucosaminidase 1 (HYAL1) presenting as familial juvenile idiopathic arthritis.J Inherit Metab Dis. 2011 Oct;34(5):1013-22. doi: 10.1007/s10545-011-9343-3. Epub 2011 May 11.
• [9] [Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].Mol Biol (Mosk). 2008 Nov-Dec;42(6):965-76.
• [10] Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model.Am J Pathol. 2006 Oct;169(4):1415-26. doi: 10.2353/ajpath.2006.060324.
• [11] Serum hyaluronidase aberrations in metabolic and morphogenetic disorders.Glycoconj J. 2005 Nov;22(7-9):395-400. doi: 10.1007/s10719-005-1390-2.
• [12] Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model.Sci Rep. 2017 Aug 1;7(1):7028. doi: 10.1038/s41598-017-07376-5.
• [13] Hyaluronan synthases and hyaluronidases in nasal polyps.Eur Arch Otorhinolaryngol. 2016 Jul;273(7):1801-8. doi: 10.1007/s00405-015-3848-6. Epub 2015 Dec 10.
• [14] Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling.Matrix Biol. 2019 May;78-79:165-179. doi: 10.1016/j.matbio.2018.05.002. Epub 2018 May 10.
• [15] The enzymatic degradation of hyaluronan is associated with disease progression in experimental pulmonary hypertension.Am J Physiol Lung Cell Mol Physiol. 2010 Feb;298(2):L148-57. doi: 10.1152/ajplung.00097.2009. Epub 2009 Nov 13.
• [16] The investigation of hyaluronic acid and hyaluronidase-1 levels as tumour marker in larynx cancer.Clin Otolaryngol. 2019 Nov;44(6):914-918. doi: 10.1111/coa.13390. Epub 2019 Aug 1.
• [17] The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer.J Gastroenterol Hepatol. 2019 Oct;34(10):1766-1776. doi: 10.1111/jgh.14660. Epub 2019 Apr 10.
• [18] High-molecular-weight hyaluronan produced by activated pancreatic stellate cells promotes pancreatic cancer cell migration via paracrine signaling.Biochem Biophys Res Commun. 2019 Jul 30;515(3):493-498. doi: 10.1016/j.bbrc.2019.05.167. Epub 2019 Jun 3.
• [19] Serum levels of hyaluronic acid are associated with COPD severity and predict survival.Eur Respir J. 2019 Mar 7;53(3):1801183. doi: 10.1183/13993003.01183-2018. Print 2019 Mar.
• [20] Subtype specific elevated expression of hyaluronidase-1 (HYAL-1) in epithelial ovarian cancer.PLoS One. 2011;6(6):e20705. doi: 10.1371/journal.pone.0020705. Epub 2011 Jun 10.
• [21] A mouse model of human mucopolysaccharidosis IX exhibits osteoarthritis.Hum Mol Genet. 2008 Jul 1;17(13):1904-15. doi: 10.1093/hmg/ddn088. Epub 2008 Mar 15.
• [22] The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium.Cancer Res. 2000 Nov 1;60(21):6116-33.
• [23] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [26] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Differential DNA methylation profile of key genes in malignant prostate epithelial cells transformed by inorganic arsenic or cadmium. Toxicol Appl Pharmacol. 2015 Aug 1;286(3):159-67.
• [29] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [30] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [31] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [32] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [33] Contact allergen (PPD and DNCB)-induced keratinocyte sensitization is partly mediated through a low molecular weight hyaluronan (LMWHA)/TLR4/NF-B signaling axis. Toxicol Appl Pharmacol. 2019 Aug 15;377:114632. doi: 10.1016/j.taap.2019.114632. Epub 2019 Jun 19.
• [34] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [35] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [36] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [37] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [38] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.