Details of Drug Off-Target (DOT)

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

• DOT Name: Hyaluronidase-2 (HYAL2)
• Synonyms: Hyal-2; EC 3.2.1.35; Hyaluronoglucosaminidase-2; Lung carcinoma protein 2; LuCa-2
• Gene Name: HYAL2
• Related Disease:
  Adenocarcinoma
  Arthritis
  Breast cancer
  Breast carcinoma
  Carcinoma
  Colitis
  Colon cancer
  Colon carcinoma
  Endometrial carcinoma
  Inflammation
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Metastatic malignant neoplasm
  Mucopolysaccharidosis
  Mucopolysaccharidosis type 9
  Neoplasm
  Osteoarthritis
  Pulmonary hypertension
  Rheumatoid arthritis
  Squamous cell carcinoma
  Triple negative breast cancer
  Colorectal carcinoma
  Adult lymphoma
  B-cell neoplasm
  Cutaneous melanoma
  Glioma
  Lymphoma
  Minimally invasive lung adenocarcinoma
  Pediatric lymphoma
  Precancerous condition
  Small-cell lung cancer
• UniProt ID: HYAL2_HUMAN
• EC Number: 3.2.1.35
• Pfam ID: PF01630
• Sequence:
  MRAGPGPTVTLALVLAVSWAMELKPTAPPIFTGRPFVVAWDVPTQDCGPRLKVPLDLNAF
  DVQASPNEGFVNQNITIFYRDRLGLYPRFDSAGRSVHGGVPQNVSLWAHRKMLQKRVEHY
  IRTQESAGLAVIDWEDWRPVWVRNWQDKDVYRRLSRQLVASRHPDWPPDRIVKQAQYEFE
  FAAQQFMLETLRYVKAVRPRHLWGFYLFPDCYNHDYVQNWESYTGRCPDVEVARNDQLAW
  LWAESTALFPSVYLDETLASSRHGRNFVSFRVQEALRVARTHHANHALPVYVFTRPTYSR
  RLTGLSEMDLISTIGESAALGAAGVILWGDAGYTTSTETCQYLKDYLTRLLVPYVVNVSW
  ATQYCSRAQCHGHGRCVRRNPSASTFLHLSTNSFRLVPGHAPGEPQLRPVGELSWADIDH
  LQTHFRCQCYLGWSGEQCQWDHRQAAGGASEAWAGSHLTSLLALAALAFTWTL
• Function: Hydrolyzes high molecular weight hyaluronic acid to produce an intermediate-sized product which is further hydrolyzed by sperm hyaluronidase to give small oligosaccharides. Displays very low levels of activity. Associates with and negatively regulates MST1R.
• Tissue Specificity: Widely expressed. No expression detected in adult brain.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway: Hyaluronan uptake and degradation (R-HSA-2160916)
• BioCyc Pathway: MetaCyc:HS00926-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Arthritis	DIST1YEL	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Colitis	DISAF7DD	Strong	Genetic Variation	[5]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Inflammation	DISJUQ5T	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Mucopolysaccharidosis	DISB083T	Strong	Biomarker	[10]
Mucopolysaccharidosis type 9	DISFSB6J	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Osteoarthritis	DIS05URM	Strong	Biomarker	[10]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[14]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[15]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[16]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[17]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[17]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[18]
Glioma	DIS5RPEH	Limited	Altered Expression	[19]
Lymphoma	DISN6V4S	Limited	Altered Expression	[17]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Biomarker	[20]
Pediatric lymphoma	DIS51BK2	Limited	Altered Expression	[17]
Precancerous condition	DISV06FL	Limited	Biomarker	[18]
Small-cell lung cancer	DISK3LZD	Limited	Altered Expression	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Hyaluronidase-2 (HYAL2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hyaluronidase-2 (HYAL2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hyaluronidase-2 (HYAL2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hyaluronidase-2 (HYAL2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hyaluronidase-2 (HYAL2).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Hyaluronidase-2 (HYAL2).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hyaluronidase-2 (HYAL2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hyaluronidase-2 (HYAL2).	[26]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Hyaluronidase-2 (HYAL2).	[27]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Hyaluronidase-2 (HYAL2).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hyaluronidase-2 (HYAL2).	[30]

References

• [1] Identification of Hyal2 as the cell-surface receptor for jaagsiekte sheep retrovirus and ovine nasal adenocarcinoma virus.Curr Top Microbiol Immunol. 2003;275:179-99. doi: 10.1007/978-3-642-55638-8_7.
• [2] Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction.Arthritis Res Ther. 2004;6(6):R514-20. doi: 10.1186/ar1223. Epub 2004 Sep 22.
• [3] DNA methylation array analyses identified breast cancer-associated HYAL2 methylation in peripheral blood.Int J Cancer. 2015 Apr 15;136(8):1845-55. doi: 10.1002/ijc.29205. Epub 2014 Sep 24.
• [4] 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.
• [5] Platelet hyaluronidase-2 regulates the early stages of inflammatory disease in colitis.Blood. 2019 Aug 29;134(9):765-775. doi: 10.1182/blood.2018893594. Epub 2019 Jul 1.
• [6] Methylation status at HYAL2 predicts overall and progression-free survival of colon cancer patients under 5-FU chemotherapy.Genomics. 2015 Dec;106(6):348-54. doi: 10.1016/j.ygeno.2015.10.002. Epub 2015 Oct 21.
• [7] 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.
• [8] Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer.Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):482-7. doi: 10.1158/1078-0432.CCR-06-1593.
• [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] 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.
• [11] Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6296-300. doi: 10.1073/pnas.96.11.6296.
• [12] High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b.Dev Cell. 2019 May 20;49(4):590-604.e9. doi: 10.1016/j.devcel.2019.04.018. Epub 2019 May 9.
• [13] 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.
• [14] HYAL1 and HYAL2 inhibit tumour growth in vivo but not in vitro.PLoS One. 2008 Aug 22;3(8):e3031. doi: 10.1371/journal.pone.0003031.
• [15] S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer.Exp Mol Pathol. 2015 Aug;99(1):180-7. doi: 10.1016/j.yexmp.2015.06.010. Epub 2015 Jun 22.
• [16] 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.
• [17] Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness.Int J Cancer. 2005 Jan 10;113(2):207-12. doi: 10.1002/ijc.20562.
• [18] Inverse expression of hyaluronidase 2 and hyaluronan synthases 1-3 is associated with reduced hyaluronan content in malignant cutaneous melanoma.BMC Cancer. 2013 Apr 5;13:181. doi: 10.1186/1471-2407-13-181.
• [19] Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines.Oncol Rep. 2003 May-Jun;10(3):609-16.
• [20] Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4580-5. doi: 10.1073/pnas.0837136100. Epub 2003 Apr 3.
• [21] 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.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] 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.
• [27] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [28] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [29] 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.
• [30] 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.
• [31] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.