Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPM8IL8)

• DOT Name: Hyaluronan synthase 3 (HAS3)
• Synonyms: EC 2.4.1.212; Hyaluronate synthase 3; Hyaluronic acid synthase 3; HA synthase 3
• Gene Name: HAS3
• Related Disease:
  Hereditary gingival fibromatosis
  Adenocarcinoma
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bone osteosarcoma
  Carcinoma
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Fatty liver disease
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Nasal polyp
  Neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Pulmonary hypertension
  Transitional cell carcinoma
  Urothelial carcinoma
  Melanoma
  Polycystic ovarian syndrome
  Atopic dermatitis
  Cardiomyopathy
  Nephropathy
  Neuroblastoma
  Non-insulin dependent diabetes
  Rheumatoid arthritis
• UniProt ID: HYAS3_HUMAN
• EC Number: 2.4.1.212
• Pfam ID: PF13641
• Sequence:
  MPVQLTTALRVVGTSLFALAVLGGILAAYVTGYQFIHTEKHYLSFGLYGAILGLHLLIQS
  LFAFLEHRRMRRAGQALKLPSPRRGSVALCIAAYQEDPDYLRKCLRSAQRISFPDLKVVM
  VVDGNRQEDAYMLDIFHEVLGGTEQAGFFVWRSNFHEAGEGETEASLQEGMDRVRDVVRA
  STFSCIMQKWGGKREVMYTAFKALGDSVDYIQVCDSDTVLDPACTIEMLRVLEEDPQVGG
  VGGDVQILNKYDSWISFLSSVRYWMAFNVERACQSYFGCVQCISGPLGMYRNSLLQQFLE
  DWYHQKFLGSKCSFGDDRHLTNRVLSLGYRTKYTARSKCLTETPTKYLRWLNQQTRWSKS
  YFREWLYNSLWFHKHHLWMTYESVVTGFFPFFLIATVIQLFYRGRIWNILLFLLTVQLVG
  IIKATYACFLRGNAEMIFMSLYSLLYMSSLLPAKIFAIATINKSGWGTSGRKTIVVNFIG
  LIPVSIWVAVLLGGLAYTAYCQDLFSETELAFLVSGAILYGCYWVALLMLYLAIIARRCG
  KKPEQYSLAFAEV
• Function: Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer. Therefore, it is essential to hyaluronan synthesis a major component of most extracellular matrices that has a structural role in tissues architectures and regulates cell adhesion, migration and differentiation. This is one of three isoenzymes responsible for cellular hyaluronan synthesis.
• Reactome Pathway: Hyaluronan biosynthesis and export (R-HSA-2142850)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary gingival fibromatosis	DISN1ML3	Definitive	Altered Expression	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[9]
Hepatitis	DISXXX35	Strong	Biomarker	[10]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[14]
Oral cancer	DISLD42D	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[17]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[13]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[13]
Melanoma	DIS1RRCY	moderate	Altered Expression	[18]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[19]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[20]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[21]
Nephropathy	DISXWP4P	Limited	Genetic Variation	[22]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[22]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[24]

2 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 Hyaluronan synthase 3 (HAS3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hyaluronan synthase 3 (HAS3).	[36]

13 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 Hyaluronan synthase 3 (HAS3).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Hyaluronan synthase 3 (HAS3).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hyaluronan synthase 3 (HAS3).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hyaluronan synthase 3 (HAS3).	[29]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Hyaluronan synthase 3 (HAS3).	[30]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Hyaluronan synthase 3 (HAS3).	[31]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Hyaluronan synthase 3 (HAS3).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Hyaluronan synthase 3 (HAS3).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hyaluronan synthase 3 (HAS3).	[34]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Hyaluronan synthase 3 (HAS3).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Hyaluronan synthase 3 (HAS3).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Hyaluronan synthase 3 (HAS3).	[38]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Hyaluronan synthase 3 (HAS3).	[39]

References

• [1] Differences in the expression of glycosaminoglycans in human fibroblasts derived from gingival overgrowths is related to TGF-beta up-regulation.Growth Factors. 2010 Feb;28(1):24-33. doi: 10.3109/08977190903321819.
• [2] Manipulation of hyaluronan synthase expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells.J Biol Chem. 2002 Mar 22;277(12):10050-7. doi: 10.1074/jbc.M110069200. Epub 2002 Jan 14.
• [3] Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases.J Alzheimers Dis. 2017;57(2):395-409. doi: 10.3233/JAD-160804.
• [4] Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.Matrix Biol. 2018 Mar;66:67-80. doi: 10.1016/j.matbio.2017.09.005. Epub 2017 Oct 5.
• [5] HAS3-related hyaluronan enhances biological activities necessary for metastasis of osteosarcoma cells.Int J Oncol. 2006 Jul;29(1):175-83.
• [6] 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.
• [7] FAK and HAS inhibition synergistically decrease colon cancer cell viability and affect expression of critical genes.Anticancer Agents Med Chem. 2013 May;13(4):584-94. doi: 10.2174/1871520611313040008.
• [8] Inhibition of oesophageal squamous cell carcinoma progression by in vivo targeting of hyaluronan synthesis.Mol Cancer. 2011 Mar 23;10:30. doi: 10.1186/1476-4598-10-30.
• [9] Differential effects of hyaluronan synthase 3 deficiency after acute vs chronic liver injury in mice.Fibrogenesis Tissue Repair. 2016 Mar 31;9:4. doi: 10.1186/s13069-016-0041-5. eCollection 2016.
• [10] The Hepatitis Aggressiveness Score (HAS): a novel classification system for post-liver transplantation recurrent hepatitis C.Am J Surg Pathol. 2013 Jan;37(1):104-13. doi: 10.1097/PAS.0b013e31826a92ac.
• [11] Hyaluronan histochemistry-a potential new tool to assess the progress of liver disease from simple steatosis to hepatocellular carcinoma.Glycobiology. 2019 Apr 1;29(4):298-306. doi: 10.1093/glycob/cwz002.
• [12] 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.
• [13] HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder.Tumour Biol. 2015 Jul;36(7):5441-50. doi: 10.1007/s13277-015-3210-z. Epub 2015 May 2.
• [14] Triptolide suppresses the in vitro and in vivo growth of lung cancer cells by targeting hyaluronan-CD44/RHAMM signaling.Oncotarget. 2017 Apr 18;8(16):26927-26940. doi: 10.18632/oncotarget.15879.
• [15] Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer.Oncotarget. 2017 Feb 28;8(9):15563-15583. doi: 10.18632/oncotarget.14697.
• [16] Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells.Cancer Res. 2001 Jul 1;61(13):5207-14.
• [17] 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.
• [18] Hyaluronan synthase 3 (HAS3) overexpression downregulates MV3 melanoma cell proliferation, migration and adhesion.Exp Cell Res. 2015 Sep 10;337(1):1-15. doi: 10.1016/j.yexcr.2015.07.026. Epub 2015 Jul 26.
• [19] Analysis of hyaluronic acid in the endometrium of women with polycystic ovary syndrome.Gynecol Endocrinol. 2019 Feb;35(2):133-137. doi: 10.1080/09513590.2018.1505844. Epub 2019 Jan 6.
• [20] miR-10a-5p is increased in atopic dermatitis and has capacity to inhibit keratinocyte proliferation.Allergy. 2019 Nov;74(11):2146-2156. doi: 10.1111/all.13849. Epub 2019 Jun 6.
• [21] Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group.J Clin Oncol. 2014 Mar 1;32(7):647-53. doi: 10.1200/JCO.2013.50.3557. Epub 2014 Jan 27.
• [22] Further evidence for the association of MMP9 with nephropathy in type 2 diabetes and application of DNA pooling technology to candidate gene screening.J Nephrol. 2008 May-Jun;21(3):400-5.
• [23] Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3-induced mitophagy.Cancer Med. 2019 Aug;8(10):4821-4835. doi: 10.1002/cam4.2389. Epub 2019 Jul 5.
• [24] Glucocorticoids inhibit induced and non-induced mRNA accumulation of genes encoding hyaluronan synthases (HAS): hydrocortisone inhibits HAS1 activation by blocking the p38 mitogen-activated protein kinase signalling pathway.Rheumatology (Oxford). 2004 Feb;43(2):164-9. doi: 10.1093/rheumatology/keh014. Epub 2003 Sep 16.
• [25] 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.
• [26] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [31] 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.
• [32] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] 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.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [39] The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. Mol Carcinog. 2014 Oct;53(10):765-76.