Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG6VUSP)

• DOT Name: Hyaluronidase-3 (HYAL3)
• Synonyms: Hyal-3; EC 3.2.1.35; Hyaluronoglucosaminidase-3; Lung carcinoma protein 3; LuCa-3
• Gene Name: HYAL3
• Related Disease:
  Advanced cancer
  Carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Lung squamous cell carcinoma
  Metastatic malignant neoplasm
  Glaucoma/ocular hypertension
  Glioma
  Neoplasm
  OPTN-related open angle glaucoma
  Small-cell lung cancer
• UniProt ID: HYAL3_HUMAN
• EC Number: 3.2.1.35
• Pfam ID: PF01630
• Sequence:
  MTTQLGPALVLGVALCLGCGQPLPQVPERPFSVLWNVPSAHCEARFGVHLPLNALGIIAN
  RGQHFHGQNMTIFYKNQLGLYPYFGPRGTAHNGGIPQALPLDRHLALAAYQIHHSLRPGF
  AGPAVLDWEEWCPLWAGNWGRRRAYQAASWAWAQQVFPDLDPQEQLYKAYTGFEQAARAL
  MEDTLRVAQALRPHGLWGFYHYPACGNGWHSMASNYTGRCHAATLARNTQLHWLWAASSA
  LFPSIYLPPRLPPAHHQAFVRHRLEEAFRVALVGHRHPLPVLAYVRLTHRRSGRFLSQDD
  LVQSIGVSAALGAAGVVLWGDLSLSSSEEECWHLHDYLVDTLGPYVINVTRAAMACSHQR
  CHGHGRCARRDPGQMEAFLHLWPDGSLGDWKSFSCHCYWGWAGPTCQEPRPGPKEAV
• Function: Facilitates sperm penetration into the layer of cumulus cells surrounding the egg by digesting hyaluronic acid. Involved in induction of the acrosome reaction in the sperm. Involved in follicular atresia, the breakdown of immature ovarian follicles that are not selected to ovulate. Induces ovarian granulosa cell apoptosis, possibly via apoptotic signaling pathway involving CASP8 and CASP3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage. Has no hyaluronidase activity in embryonic fibroblasts in vitro. Has no hyaluronidase activity in granulosa cells in vitro.
• Tissue Specificity: Expressed in sperm . Highly expressed in epidermis of the skin, where it is expressed intracellularily in the deep horny layer (at protein level) . Bone marrow, testis and kidney .
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Hyaluronan uptake and degradation (R-HSA-2160916)
  CS/DS degradation (R-HSA-2024101)
• BioCyc Pathway: MetaCyc:ENSG00000114366-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[3]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[2]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[5]
Glioma	DIS5RPEH	Limited	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
OPTN-related open angle glaucoma	DISDR98A	Limited	Biomarker	[5]
Small-cell lung cancer	DISK3LZD	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hyaluronidase-3 (HYAL3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hyaluronidase-3 (HYAL3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hyaluronidase-3 (HYAL3).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hyaluronidase-3 (HYAL3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Hyaluronidase-3 (HYAL3).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Hyaluronidase-3 (HYAL3).	[12]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Analysis of HYAL3 gene mutations in Chinese lung squamous cell carcinoma patients.Tumori. 2013 Jan-Feb;99(1):108-12. doi: 10.1177/030089161309900118.
• [5] Genetic association and gene-gene interaction of HAS2, HABP1 and HYAL3 implicate hyaluronan metabolic genes in glaucomatous neurodegeneration.Dis Markers. 2012;33(3):145-54. doi: 10.1155/2012/390539.
• [6] Expression and regulation patterns of hyaluronidases in small cell lung cancer and glioma lines.Oncol Rep. 2003 May-Jun;10(3):609-16.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.