Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJIAG1W)

• DOT Name: Hyaluronan synthase 1 (HAS1)
• Synonyms: EC 2.4.1.212; Hyaluronate synthase 1; Hyaluronic acid synthase 1; HA synthase 1; HuHAS1
• Gene Name: HAS1
• Related Disease:
  Adenocarcinoma
  Alzheimer disease
  Arthritis
  Bladder cancer
  Endometriosis
  Epithelial neoplasm
  Gastric cancer
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Keloid
  Metastatic malignant neoplasm
  Osteoarthritis
  Plasma cell myeloma
  Pulmonary hypertension
  Rheumatoid arthritis
  Small lymphocytic lymphoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Waldenstrom macroglobulinemia
  Advanced cancer
  Polycystic ovarian syndrome
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Endometrium neoplasm
  Neoplasm
  Renal cell carcinoma
• UniProt ID: HYAS1_HUMAN
• EC Number: 2.4.1.212
• Pfam ID: PF13641
• Sequence:
  MRQQDAPKPTPAACRCSGLARRVLTIAFALLILGLMTWAYAAGVPLASDRYGLLAFGLYG
  AFLSAHLVAQSLFAYLEHRRVAAAARGPLDAATARSVALTISAYQEDPAYLRQCLASARA
  LLYPRARLRVLMVVDGNRAEDLYMVDMFREVFADEDPATYVWDGNYHQPWEPAAAGAVGA
  GAYREVEAEDPGRLAVEALVRTRRCVCVAQRWGGKREVMYTAFKALGDSVDYVQVCDSDT
  RLDPMALLELVRVLDEDPRVGAVGGDVRILNPLDSWVSFLSSLRYWVAFNVERACQSYFH
  CVSCISGPLGLYRNNLLQQFLEAWYNQKFLGTHCTFGDDRHLTNRMLSMGYATKYTSRSR
  CYSETPSSFLRWLSQQTRWSKSYFREWLYNALWWHRHHAWMTYEAVVSGLFPFFVAATVL
  RLFYAGRPWALLWVLLCVQGVALAKAAFAAWLRGCLRMVLLSLYAPLYMCGLLPAKFLAL
  VTMNQSGWGTSGRRKLAANYVPLLPLALWALLLLGGLVRSVAHEARADWSGPSRAAEAYH
  LAAGAGAYVGYWVAMLTLYWVGVRRLCRRRTGGYRVQV
• 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 the isozymes catalyzing that reaction. Also able to catalyze the synthesis of chito-oligosaccharide depending on the substrate.
• Tissue Specificity: Widely expressed. Highly expressed in ovary followed by spleen, thymus, prostate, testes and large intestine. Weakly expressed in small intestine.
• Reactome Pathway: Hyaluronan biosynthesis and export (R-HSA-2142850)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Arthritis	DIST1YEL	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Endometriosis	DISX1AG8	Strong	Altered Expression	[5]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Hepatitis	DISXXX35	Strong	Biomarker	[8]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Keloid	DISV09JY	Strong	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[11]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[12]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[3]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Waldenstrom macroglobulinemia	DIS9O23I	Strong	Genetic Variation	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[14]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[15]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[12]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[12]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[16]
Endometrium neoplasm	DIS6OS2L	Limited	Altered Expression	[17]
Neoplasm	DISZKGEW	Limited	Altered Expression	[18]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Hyaluronan synthase 1 (HAS1).	[19]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Hyaluronan synthase 1 (HAS1).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Hyaluronan synthase 1 (HAS1).	[21]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Hyaluronan synthase 1 (HAS1).	[21]
Guaiacol	DMN4E7T	Phase 3	Guaiacol decreases the expression of Hyaluronan synthase 1 (HAS1).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Hyaluronan synthase 1 (HAS1).	[21]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Hyaluronan synthase 1 (HAS1).	[22]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Hyaluronan synthase 1 (HAS1).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Hyaluronan synthase 1 (HAS1).	[24]
Chlorogenic acid	DM2Y3P4	Investigative	Chlorogenic acid increases the expression of Hyaluronan synthase 1 (HAS1).	[21]

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 affects the methylation of Hyaluronan synthase 1 (HAS1).	[23]

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] 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.
• [3] 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.
• [4] The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder.PLoS One. 2013 Sep 17;8(9):e75681. doi: 10.1371/journal.pone.0075681. eCollection 2013.
• [5] The Hyaluronic Acid System is Intact in Menstrual Endometrial Cells in Women With and Without Endometriosis.Reprod Sci. 2019 Jan;26(1):109-113. doi: 10.1177/1933719118766257. Epub 2018 Apr 5.
• [6] Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.BMC Cancer. 2009 May 12;9:143. doi: 10.1186/1471-2407-9-143.
• [7] miR-125a restrains cell migration and invasion by targeting STAT3 in gastric cancer cells.Onco Targets Ther. 2018 Dec 24;12:205-215. doi: 10.2147/OTT.S168454. eCollection 2019.
• [8] 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.
• [9] 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.
• [10] Characterization of In Vitro Reconstructed Human Normotrophic, Hypertrophic, and Keloid Scar Models.Tissue Eng Part C Methods. 2018 Apr;24(4):242-253. doi: 10.1089/ten.TEC.2017.0464. Epub 2018 Apr 2.
• [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] Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.PLoS One. 2014 Jun 20;9(6):e100691. doi: 10.1371/journal.pone.0100691. eCollection 2014.
• [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] Human hyaluronic acid synthase-1 promotes malignant transformation via epithelial-to-mesenchymal transition, micronucleation and centrosome abnormalities.Cell Commun Signal. 2017 Nov 14;15(1):48. doi: 10.1186/s12964-017-0204-z.
• [15] 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.
• [16] MicroRNA-125a suppresses cell migration, invasion, and regulates hyaluronic acid synthase 1 expression by targeting signal transducers and activators of transcription 3 in renal cell carcinoma cells.J Cell Biochem. 2019 Feb;120(2):1894-1902. doi: 10.1002/jcb.27503. Epub 2018 Sep 6.
• [17] Role of hyaluronan and hyaluronan synthase in endometrial cancer.Oncol Rep. 2005 Jun;13(6):1101-5.
• [18] Hyaluronic acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44.Cancer Res. 2008 Jan 15;68(2):483-91. doi: 10.1158/0008-5472.CAN-07-2140.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [21] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [22] 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.
• [23] 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.
• [24] Effects of methyl paraben on skin keratinocytes. J Appl Toxicol. 2007 Jan-Feb;27(1):1-9. doi: 10.1002/jat.1176.