Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTD3PAL)

• DOT Name: Hyaluronan synthase 2 (HAS2)
• Synonyms: EC 2.4.1.212; Hyaluronate synthase 2; Hyaluronic acid synthase 2; HA synthase 2
• Gene Name: HAS2
• Related Disease:
  Adenocarcinoma
  Arteriosclerosis
  Astrocytoma
  Atherosclerosis
  Barrett esophagus
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Diabetes insipidus
  Diabetic kidney disease
  Glioma
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Non-small-cell lung cancer
  Obesity
  Oral cancer
  Plasma cell myeloma
  Pulmonary hypertension
  Renal fibrosis
  Squamous cell carcinoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma
  Chronic obstructive pulmonary disease
  Melanoma
  Polycystic ovarian syndrome
  Pulmonary fibrosis
  Advanced cancer
  Asthma
  Bone osteosarcoma
  Disease of orbital part of eye adnexa
  Fetal growth restriction
  Hyperglycemia
  Invasive breast carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Nephropathy
  Osteosarcoma
  Parkinson disease
• UniProt ID: HYAS2_HUMAN
• EC Number: 2.4.1.212
• Pfam ID: PF03142
• Sequence:
  MHCERFLCILRIIGTTLFGVSLLLGITAAYIVGYQFIQTDNYYFSFGLYGAFLASHLIIQ
  SLFAFLEHRKMKKSLETPIKLNKTVALCIAAYQEDPDYLRKCLQSVKRLTYPGIKVVMVI
  DGNSEDDLYMMDIFSEVMGRDKSATYIWKNNFHEKGPGETDESHKESSQHVTQLVLSNKS
  ICIMQKWGGKREVMYTAFRALGRSVDYVQVCDSDTMLDPASSVEMVKVLEEDPMVGGVGG
  DVQILNKYDSWISFLSSVRYWMAFNIERACQSYFGCVQCISGPLGMYRNSLLHEFVEDWY
  NQEFMGNQCSFGDDRHLTNRVLSLGYATKYTARSKCLTETPIEYLRWLNQQTRWSKSYFR
  EWLYNAMWFHKHHLWMTYEAIITGFFPFFLIATVIQLFYRGKIWNILLFLLTVQLVGLIK
  SSFASCLRGNIVMVFMSLYSVLYMSSLLPAKMFAIATINKAGWGTSGRKTIVVNFIGLIP
  VSVWFTILLGGVIFTIYKESKRPFSESKQTVLIVGTLLYACYWVMLLTLYVVLINKCGRR
  KKGQQYDMVLDV
• Function: Catalyzes the addition of GlcNAc or GlcUA monosaccharides to the nascent hyaluronan polymer (Probable). 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 and it is particularly responsible for the synthesis of high molecular mass hyaluronan.
• Tissue Specificity: Expressed in fibroblasts.
• Reactome Pathway: Hyaluronan biosynthesis and export (R-HSA-2142850)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Diabetes insipidus	DIS0U6CJ	Strong	Biomarker	[9]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Obesity	DIS47Y1K	Strong	Altered Expression	[14]
Oral cancer	DISLD42D	Strong	Altered Expression	[15]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[16]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[17]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[18]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[19]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[20]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[21]
Melanoma	DIS1RRCY	moderate	Biomarker	[22]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[23]
Pulmonary fibrosis	DISQKVLA	moderate	Biomarker	[24]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[25]
Asthma	DISW9QNS	Limited	Biomarker	[26]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[19]
Disease of orbital part of eye adnexa	DISGWPWX	Limited	Biomarker	[27]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[28]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[29]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[30]
Lung cancer	DISCM4YA	Limited	Altered Expression	[31]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[31]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[32]
Nephropathy	DISXWP4P	Limited	Genetic Variation	[33]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[19]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[34]

22 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 Hyaluronan synthase 2 (HAS2).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Hyaluronan synthase 2 (HAS2).	[36]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Hyaluronan synthase 2 (HAS2).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hyaluronan synthase 2 (HAS2).	[38]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Hyaluronan synthase 2 (HAS2).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hyaluronan synthase 2 (HAS2).	[40]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Hyaluronan synthase 2 (HAS2).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Hyaluronan synthase 2 (HAS2).	[42]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Hyaluronan synthase 2 (HAS2).	[43]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Hyaluronan synthase 2 (HAS2).	[42]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Hyaluronan synthase 2 (HAS2).	[44]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Hyaluronan synthase 2 (HAS2).	[45]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Hyaluronan synthase 2 (HAS2).	[46]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Hyaluronan synthase 2 (HAS2).	[47]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Hyaluronan synthase 2 (HAS2).	[48]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Hyaluronan synthase 2 (HAS2).	[49]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Hyaluronan synthase 2 (HAS2).	[50]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hyaluronan synthase 2 (HAS2).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hyaluronan synthase 2 (HAS2).	[53]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Hyaluronan synthase 2 (HAS2).	[54]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Hyaluronan synthase 2 (HAS2).	[55]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Hyaluronan synthase 2 (HAS2).	[56]

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 decreases the methylation of Hyaluronan synthase 2 (HAS2).	[51]

References

• [1] 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.
• [2] Induction of hyaluronic acid synthase 2 (HAS2) in human vascular smooth muscle cells by vasodilatory prostaglandins.Circ Res. 2004 Mar 19;94(5):592-600. doi: 10.1161/01.RES.0000119169.87429.A0. Epub 2004 Jan 29.
• [3] Elevated expression of hyaluronan synthase 2 associates with decreased survival in diffusely infiltrating astrocytomas.BMC Cancer. 2018 Jun 18;18(1):664. doi: 10.1186/s12885-018-4569-1.
• [4] Identification and molecular analysis of glycosaminoglycans in cutaneous lupus erythematosus and dermatomyositis.J Histochem Cytochem. 2011 Mar;59(3):336-45. doi: 10.1369/0022155410398000. Epub 2011 Jan 12.
• [5] Loss of Glycogen Debranching Enzyme AGL Drives Bladder Tumor Growth via Induction of Hyaluronic Acid Synthesis.Clin Cancer Res. 2016 Mar 1;22(5):1274-83. doi: 10.1158/1078-0432.CCR-15-1706. Epub 2015 Oct 21.
• [6] Has2 natural antisense RNA and Hmga2 promote Has2 expression during TGF-induced EMT in breast cancer.Matrix Biol. 2019 Jul;80:29-45. doi: 10.1016/j.matbio.2018.09.002. Epub 2018 Sep 5.
• [7] Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells.Int J Cancer. 2007 Jun 15;120(12):2557-67. doi: 10.1002/ijc.22550.
• [8] Hyaluronic acid synthase 2 promotes malignant phenotypes of colorectal cancer cells through transforming growth factor beta signaling.Cancer Sci. 2019 Jul;110(7):2226-2236. doi: 10.1111/cas.14070. Epub 2019 Jun 12.
• [9] Expression of type II hyaluronan-synthase gene in kidneys Wistar and Brattleboro rats with diabetes insipidus: effect of vasopressin and its analogues.Dokl Biochem Biophys. 2009 Mar-Apr;425:61-4. doi: 10.1134/s160767290902001x.
• [10] Renal hyaluronan content during experimental uncontrolled diabetes in rats.J Physiol Pharmacol. 2008 Mar;59(1):115-28.
• [11] 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.
• [12] Clinical significance of hyaluronan levels and its pro-osteogenic effect on mesenchymal stromal cells in myelodysplastic syndromes.J Transl Med. 2018 Aug 24;16(1):234. doi: 10.1186/s12967-018-1614-4.
• [13] Glycogen debranching enzyme (AGL) is a novel regulator of non-small cell lung cancer growth.Oncotarget. 2018 Mar 30;9(24):16718-16730. doi: 10.18632/oncotarget.24676. eCollection 2018 Mar 30.
• [14] Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival.Breast Cancer Res Treat. 2014 Jan;143(2):277-86. doi: 10.1007/s10549-013-2804-7. Epub 2013 Dec 14.
• [15] Hyaluronan synthase 2 expressed by cancer-associated fibroblasts promotes oral cancer invasion.J Exp Clin Cancer Res. 2016 Nov 25;35(1):181. doi: 10.1186/s13046-016-0458-0.
• [16] Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients.Blood. 2002 Oct 1;100(7):2578-85. doi: 10.1182/blood-2002-01-0030.
• [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] The human hyaluronan synthase 2 (HAS2) gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell.J Biol Chem. 2011 Jun 3;286(22):19523-32. doi: 10.1074/jbc.M111.233916. Epub 2011 Feb 25.
• [19] Silencing of HAS2-AS1 mediates PI3K/AKT signaling pathway to inhibit cell proliferation, migration, and invasion in glioma.J Cell Biochem. 2019 Jul;120(7):11510-11516. doi: 10.1002/jcb.28430. Epub 2019 Feb 20.
• [20] The synthetic pyrethroid deltamethrin impairs zebrafish (Danio rerio) swim bladder development.Sci Total Environ. 2020 Jan 20;701:134870. doi: 10.1016/j.scitotenv.2019.134870. Epub 2019 Oct 31.
• [21] Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease.Am J Respir Cell Mol Biol. 2013 Dec;49(6):1038-47. doi: 10.1165/rcmb.2013-0089OC.
• [22] Melanoma cells control HA synthesis in peritumoral fibroblasts via PDGF-AA and PDGF-CC: impact on melanoma cell proliferation.J Invest Dermatol. 2012 Feb;132(2):385-93. doi: 10.1038/jid.2011.325. Epub 2011 Oct 13.
• [23] 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.
• [24] Mitogen-activated Protein Kinase-activated Protein Kinase 2 Inhibition Attenuates Fibroblast Invasion and Severe Lung Fibrosis.Am J Respir Cell Mol Biol. 2019 Jan;60(1):41-48. doi: 10.1165/rcmb.2018-0033OC.
• [25] Dissecting the role of hyaluronan synthases in the tumor microenvironment.FEBS J. 2019 Aug;286(15):2937-2949. doi: 10.1111/febs.14847. Epub 2019 Apr 22.
• [26] Fibroblast gene expression following asthmatic bronchial epithelial cell conditioning correlates with epithelial donor lung function and exacerbation history.Sci Rep. 2018 Oct 25;8(1):15768. doi: 10.1038/s41598-018-34021-6.
• [27] Reversal of Pathological Features of Graves' Orbitopathy by Activation of Forkhead Transcription Factors, FOXOs.J Clin Endocrinol Metab. 2016 Jan;101(1):114-22. doi: 10.1210/jc.2015-2932. Epub 2015 Oct 26.
• [28] Transcriptomic Analysis Reveals Novel Mechanisms Mediating Islet Dysfunction in the Intrauterine Growth-Restricted Rat.Endocrinology. 2018 Feb 1;159(2):1035-1049. doi: 10.1210/en.2017-00888.
• [29] Peroxisome proliferator-activated receptor agonists attenuate hyperglycaemia-induced hyaluronan secretion in vascular smooth muscle cells by inhibiting PKC2.Cell Biochem Biophys. 2013 Nov;67(2):583-90. doi: 10.1007/s12013-013-9545-4.
• [30] Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer.Cancer Res. 2005 Jul 15;65(14):6139-50. doi: 10.1158/0008-5472.CAN-04-1622.
• [31] The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function.Oncogenesis. 2017 Jun 12;6(6):e348. doi: 10.1038/oncsis.2017.45.
• [32] Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer.Mol Cancer. 2019 May 20;18(1):96. doi: 10.1186/s12943-019-1023-1.
• [33] 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.
• [34] Marginal association between SNP rs2046571 of the HAS2 gene and Parkinson's disease in the Chinese female population.Neurosci Lett. 2013 Sep 27;552:58-61. doi: 10.1016/j.neulet.2013.07.031. Epub 2013 Jul 31.
• [35] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [36] 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.
• [37] 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.
• [38] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [39] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [40] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [41] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [42] 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.
• [43] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [44] Dermal hyaluronan is rapidly reduced by topical treatment with glucocorticoids. J Invest Dermatol. 2010 Jan;130(1):141-9. doi: 10.1038/jid.2009.210.
• [45] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [46] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [47] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [48] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [49] 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.
• [50] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [51] 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.
• [52] Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19408-13. doi: 10.1073/pnas.1216363109. Epub 2012 Nov 5.
• [53] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [54] 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.
• [55] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [56] Effects of methyl paraben on skin keratinocytes. J Appl Toxicol. 2007 Jan-Feb;27(1):1-9. doi: 10.1002/jat.1176.