Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHN1IKA)

• DOT Name: Integrin alpha-9 (ITGA9)
• Synonyms: Integrin alpha-RLC
• Gene Name: ITGA9
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Advanced cancer
  Bipolar disorder
  Breast neoplasm
  Carcinoma
  Cholangiocarcinoma
  Depression
  Familial hypertrophic cardiomyopathy
  Head-neck squamous cell carcinoma
  Hereditary nonpolyposis colon cancer
  Lung cancer
  Lung neoplasm
  Lynch syndrome
  Medulloblastoma
  Non-small-cell lung cancer
  Primary myelofibrosis
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Squamous cell carcinoma
  Triple negative breast cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Clear cell renal carcinoma
  Lung carcinoma
  Rheumatoid arthritis
  Amyotrophic lateral sclerosis type 1
  Hepatocellular carcinoma
  Melanoma
  Metastatic melanoma
• UniProt ID: ITA9_HUMAN
• Pfam ID: PF01839 ; PF08441 ; PF20805 ; PF20806
• Sequence:
  MGGPAAPRGAGRLRALLLALVVAGIPAGAYNLDPQRPVHFQGPADSFFGYAVLEHFHDNT
  RWVLVGAPKADSKYSPSVKSPGAVFKCRVHTNPDRRCTELDMARGKNRGTSCGKTCREDR
  DDEWMGVSLARQPKADGRVLACAHRWKNIYYEADHILPHGFCYIIPSNLQAKGRTLIPCY
  EEYKKKYGEEHGSCQAGIAGFFTEELVVMGAPGSFYWAGTIKVLNLTDNTYLKLNDEVIM
  NRRYTYLGYAVTAGHFSHPSTIDVVGGAPQDKGIGKVYIFRADRRSGTLIKIFQASGKKM
  GSYFGSSLCAVDLNGDGLSDLLVGAPMFSEIRDEGQVTVYINRGNGALEEQLALTGDGAY
  NAHFGESIASLDDLDNDGFPDVAIGAPKEDDFAGAVYIYHGDAGGIVPQYSMKLSGQKIN
  PVLRMFGQSISGGIDMDGNGYPDVTVGAFMSDSVVLLRARPVITVDVSIFLPGSINITAP
  QCHDGQQPVNCLNVTTCFSFHGKHVPGEIGLNYVLMADVAKKEKGQMPRVYFVLLGETMG
  QVTEKLQLTYMEETCRHYVAHVKRRVQDVISPIVFEAAYSLSEHVTGEEERELPPLTPVL
  RWKKGQKIAQKNQTVFERNCRSEDCAADLQLQGKLLLSSMDEKTLYLALGAVKNISLNIS
  ISNLGDDAYDANVSFNVSRELFFINMWQKEEMGISCELLESDFLKCSVGFPFMRSKSKYE
  FSVIFDTSHLSGEEEVLSFIVTAQSGNTERSESLHDNTLVLMVPLMHEVDTSITGIMSPT
  SFVYGESVDAANFIQLDDLECHFQPINITLQVYNTGPSTLPGSSVSISFPNRLSSGGAEM
  FHVQEMVVGQEKGNCSFQKNPTPCIIPQEQENIFHTIFAFFTKSGRKVLDCEKPGISCLT
  AHCNFSALAKEESRTIDIYMLLNTEILKKDSSSVIQFMSRAKVKVDPALRVVEIAHGNPE
  EVTVVFEALHNLEPRGYVVGWIIAISLLVGILIFLLLAVLLWKMGFFRRRYKEIIEAEKN
  RKENEDSWDWVQKNQ
• Function: Integrin alpha-9/beta-1 (ITGA9:ITGB1) is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. ITGA9:ITGB1 may play a crucial role in SVEP1/polydom-mediated myoblast cell adhesion. Integrin ITGA9:ITGB1 represses PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells via its interaction with SVEP1, thereby inhibiting vasocontraction.
• Tissue Specificity: Expressed in vascular smooth muscle cells (at protein level) . Expressed in the airway epithelium (at protein level) .
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (hsa04514)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Human papillomavirus infection (hsa05165)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  ECM proteoglycans (R-HSA-3000178)
  Signal transduction by L1 (R-HSA-445144)
  Integrin cell surface interactions (R-HSA-216083)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	Genetic Variation	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[9]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[11]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[12]
Lynch syndrome	DIS3IW5F	Strong	Genetic Variation	[10]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[14]
Primary myelofibrosis	DIS6L0CN	Strong	Altered Expression	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[14]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	moderate	Genetic Variation	[17]
Cervical Intraepithelial neoplasia	DISXP757	moderate	Biomarker	[17]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[18]
Lung carcinoma	DISTR26C	moderate	Biomarker	[19]
Rheumatoid arthritis	DISTSB4J	Disputed	Altered Expression	[20]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Limited	Genetic Variation	[21]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[22]
Melanoma	DIS1RRCY	Limited	Altered Expression	[23]
Metastatic melanoma	DISSL43L	Limited	Altered Expression	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Integrin alpha-9 (ITGA9).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Integrin alpha-9 (ITGA9).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Integrin alpha-9 (ITGA9).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin alpha-9 (ITGA9).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrin alpha-9 (ITGA9).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Integrin alpha-9 (ITGA9).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Integrin alpha-9 (ITGA9).	[28]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Integrin alpha-9 (ITGA9).	[29]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Integrin alpha-9 (ITGA9).	[30]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Integrin alpha-9 (ITGA9).	[31]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Integrin alpha-9 (ITGA9).	[29]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Integrin alpha-9 (ITGA9).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Integrin alpha-9 (ITGA9).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Integrin alpha-9 (ITGA9).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin alpha-9 (ITGA9).	[36]

References

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• [2] Integrin 9 depletion promotes -catenin degradation to suppress triple-negative breast cancer tumor growth and metastasis.Int J Cancer. 2019 Nov 15;145(10):2767-2780. doi: 10.1002/ijc.32359. Epub 2019 May 3.
• [3] Refinement of chromosome 3p22.3 region and identification of a susceptibility gene for bipolar affective disorder.Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):163-8. doi: 10.1002/ajmg.b.32127. Epub 2012 Dec 31.
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• [5] Inactivation of the human fragile histidine triad gene at 3p14.2 in monochromosomal human/mouse microcell hybrid-derived severe combined immunodeficient mouse tumors.Cancer Res. 2000 Dec 15;60(24):7119-25.
• [6] A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy.Prenat Diagn. 2008 Nov;28(11):1057-63. doi: 10.1002/pd.2130.
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• [9] Frequent alterations of the candidate genes hMLH1, ITGA9 and RBSP3 in early dysplastic lesions of head and neck: clinical and prognostic significance.Cancer Sci. 2010 Jun;101(6):1511-20. doi: 10.1111/j.1349-7006.2010.01551.x. Epub 2010 Feb 4.
• [10] An interstitial deletion at 3p21.3 results in the genetic fusion of MLH1 and ITGA9 in a Lynch syndrome family.Clin Cancer Res. 2009 Feb 1;15(3):762-9. doi: 10.1158/1078-0432.CCR-08-1908.
• [11] Aberrant upregulation of a novel integrin alpha subunit gene at 3p21.3 in small cell lung cancer.Oncogene. 1994 Feb;9(2):611-9.
• [12] [Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].Mol Biol (Mosk). 2008 Nov-Dec;42(6):965-76.
• [13] Integrins mediate adhesion of medulloblastoma cells to tenascin and activate pathways associated with survival and proliferation.Lab Invest. 2008 Nov;88(11):1143-56. doi: 10.1038/labinvest.2008.89. Epub 2008 Sep 15.
• [14] Expression level and methylation status of three tumor suppressor genes, DLEC1, ITGA9 and MLH1, in non-small cell lung cancer.Med Oncol. 2016 Jul;33(7):75. doi: 10.1007/s12032-016-0791-3. Epub 2016 Jun 10.
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• [16] Tenascin-C and Integrin 9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment.Cancer Res. 2017 Nov 1;77(21):5977-5988. doi: 10.1158/0008-5472.CAN-17-0064. Epub 2017 Sep 15.
• [17] RBSP3 is frequently altered in premalignant cervical lesions: clinical and prognostic significance.Genes Chromosomes Cancer. 2010 Feb;49(2):155-70. doi: 10.1002/gcc.20726.
• [18] Morphine enhances renal cell carcinoma aggressiveness through promotes survivin level.Ren Fail. 2017 Nov;39(1):258-264. doi: 10.1080/0886022X.2016.1256322. Epub 2016 Nov 21.
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• [22] Integrin 9 Suppresses Hepatocellular Carcinoma Metastasis by Rho GTPase Signaling.J Immunol Res. 2018 May 24;2018:4602570. doi: 10.1155/2018/4602570. eCollection 2018.
• [23] MicroRNA-125b suppresses the epithelial-mesenchymal transition and cell invasion by targeting ITGA9 in melanoma.Tumour Biol. 2016 May;37(5):5941-9. doi: 10.1007/s13277-015-4409-8. Epub 2015 Nov 23.
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• [29] 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.
• [30] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [31] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [32] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [33] 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.
• [34] 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.
• [35] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [36] 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.