Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPTK5VS)

• DOT Name: Heparanase (HPSE)
• Synonyms: EC 3.2.1.166; Endo-glucoronidase; Heparanase-1; Hpa1
• Gene Name: HPSE
• UniProt ID: HPSE_HUMAN
• PDB ID: 5E8M; 5E97; 5E98; 5E9B; 5E9C; 5L9Y; 5L9Z; 5LA4; 5LA7; 6ZDM; 7PR7; 7PR8; 7PRT; 7RG8; 7YI7; 7YJC; 8B0B; 8B0C; 8BAC; 8E07; 8E08; 8JYG
• EC Number: 3.2.1.166
• Pfam ID: PF03662
• Sequence:
  MLLRSKPALPPPLMLLLLGPLGPLSPGALPRPAQAQDVVDLDFFTQEPLHLVSPSFLSVT
  IDANLATDPRFLILLGSPKLRTLARGLSPAYLRFGGTKTDFLIFDPKKESTFEERSYWQS
  QVNQDICKYGSIPPDVEEKLRLEWPYQEQLLLREHYQKKFKNSTYSRSSVDVLYTFANCS
  GLDLIFGLNALLRTADLQWNSSNAQLLLDYCSSKGYNISWELGNEPNSFLKKADIFINGS
  QLGEDFIQLHKLLRKSTFKNAKLYGPDVGQPRRKTAKMLKSFLKAGGEVIDSVTWHHYYL
  NGRTATKEDFLNPDVLDIFISSVQKVFQVVESTRPGKKVWLGETSSAYGGGAPLLSDTFA
  AGFMWLDKLGLSARMGIEVVMRQVFFGAGNYHLVDENFDPLPDYWLSLLFKKLVGTKVLM
  ASVQGSKRRKLRVYLHCTNTDNPRYKEGDLTLYAINLHNVTKYLRLPYPFSNKQVDKYLL
  RPLGPHGLLSKSVQLNGLTLKMVDDQTLPPLMEKPLRPGSSLGLPAFSYSFFVIRNAKVA
  ACI
• Function: Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as a procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extracellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.
• Tissue Specificity: Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Also expressed in hair follicles, specifically in both Henle's and Huxley's layers of inner the root sheath (IRS) at anagen phase.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  HS-GAG degradation (R-HSA-2024096)
• BioCyc Pathway: MetaCyc:ENSG00000173083-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Heparanase (HPSE).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Heparanase (HPSE).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Heparanase (HPSE).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Heparanase (HPSE).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heparanase (HPSE).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Heparanase (HPSE).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Heparanase (HPSE).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heparanase (HPSE).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Heparanase (HPSE).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Heparanase (HPSE).	[10]
Propofol	DMB4OLE	Approved	Propofol increases the expression of Heparanase (HPSE).	[11]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of Heparanase (HPSE).	[11]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Heparanase (HPSE).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heparanase (HPSE).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Heparanase (HPSE).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Heparanase (HPSE).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Heparanase (HPSE).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heparanase (HPSE).	[13]

References

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• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Gene expression profiling of human peri-implantation endometria between natural and stimulated cycles. Fertil Steril. 2008 Dec;90(6):2152-64.
• [6] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [7] 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.
• [8] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [9] Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia. 2008 Mar;10(3):266-78. doi: 10.1593/neo.07947.
• [10] 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.
• [11] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [12] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [13] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.