Details of Drug Off-Target (DOT)

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

• DOT Name: Semaphorin-5A (SEMA5A)
• Synonyms: Semaphorin-F; Sema F
• Gene Name: SEMA5A
• Related Disease:
  Non-small-cell lung cancer
  Stomach cancer
  Advanced cancer
  Alcohol dependence
  Alzheimer disease
  Astrocytoma
  Autism spectrum disorder
  Autoimmune disease
  Cervical cancer
  Cervical carcinoma
  Cognitive impairment
  Colon cancer
  Colon carcinoma
  Cryohydrocytosis
  Endometrial cancer
  Endometrial carcinoma
  Gastric cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Myasthenia gravis
  Neoplasm
  Nephritis
  Pancreatic cancer
  Pancreatic tumour
  Parkinson disease
  Pervasive developmental disorder
  Systemic lupus erythematosus
  Acute myelogenous leukaemia
  Autism
  Coronary heart disease
  Plasma cell myeloma
  Intellectual disability
  Melanoma
  Stroke
• UniProt ID: SEM5A_HUMAN
• Pfam ID: PF01437 ; PF01403 ; PF00090
• Sequence:
  MKGTCVIAWLFSSLGLWRLAHPEAQGTTQCQRTEHPVISYKEIGPWLREFRAKNAVDFSQ
  LTFDPGQKELVVGARNYLFRLQLEDLSLIQAVEWECDEATKKACYSKGKSKEECQNYIRV
  LLVGGDRLFTCGTNAFTPVCTNRSLSNLTEIHDQISGMARCPYSPQHNSTALLTAGGELY
  AATAMDFPGRDPAIYRSLGILPPLRTAQYNSKWLNEPNFVSSYDIGNFTYFFFRENAVEH
  DCGKTVFSRAARVCKNDIGGRFLLEDTWTTFMKARLNCSRPGEVPFYYNELQSTFFLPEL
  DLIYGIFTTNVNSIAASAVCVFNLSAIAQAFSGPFKYQENSRSAWLPYPNPNPHFQCGTV
  DQGLYVNLTERNLQDAQKFILMHEVVQPVTTVPSFMEDNSRFSHVAVDVVQGREALVHII
  YLATDYGTIKKVRVPLNQTSSSCLLEEIELFPERRREPIRSLQILHSQSVLFVGLREHVV
  KIPLKRCQFYRTRSTCIGAQDPYCGWDVVMKKCTSLEESLSMTQWEQSISACPTRNLTVD
  GHFGVWSPWTPCTHTDGSAVGSCLCRTRSCDSPAPQCGGWQCEGPGMEIANCSRNGGWTP
  WTSWSPCSTTCGIGFQVRQRSCSNPTPRHGGRVCVGQNREERYCNEHLLCPPHMFWTGWG
  PWERCTAQCGGGIQARRRICENGPDCAGCNVEYQSCNTNPCPELKKTTPWTPWTPVNISD
  NGGHYEQRFRYTCKARLADPNLLEVGRQRIEMRYCSSDGTSGCSTDGLSGDFLRAGRYSA
  HTVNGAWSAWTSWSQCSRDCSRGIRNRKRVCNNPEPKYGGMPCLGPSLEYQECNILPCPV
  DGVWSCWSPWTKCSATCGGGHYMRTRSCSNPAPAYGGDICLGLHTEEALCNTQPCPESWS
  EWSDWSECEASGVQVRARQCILLFPMGSQCSGNTTESRPCVFDSNFIPEVSVARSSSVEE
  KRCGEFNMFHMIAVGLSSSILGCLLTLLVYTYCQRYQQQSHDATVIHPVSPAPLNTSITN
  HINKLDKYDSVEAIKAFNKNNLILEERNKYFNPHLTGKTYSNAYFTDLNNYDEY
• Function: Bifunctional axonal guidance cue regulated by sulfated proteoglycans; attractive effects result from interactions with heparan sulfate proteoglycans (HSPGs), while the inhibitory effects depend on interactions with chondroitin sulfate proteoglycans (CSPGs). Ligand for receptor PLXNB3. In glioma cells, SEMA5A stimulation of PLXNB3 results in the disassembly of F-actin stress fibers, disruption of focal adhesions and cellular collapse as well as inhibition of cell migration and invasion through ARHGDIA-mediated inactivation of RAC1. May promote angiogenesis by increasing endothelial cell proliferation and migration and inhibiting apoptosis.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Defective B3GALTL causes PpS (R-HSA-5083635)
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Other semaphorin interactions (R-HSA-416700)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Biomarker	[8]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[8]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Cryohydrocytosis	DISMQHL3	Strong	Biomarker	[10]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[11]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[15]
Nephritis	DISQZQ70	Strong	Altered Expression	[7]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[15]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[16]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[17]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[18]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[7]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[19]
Autism	DISV4V1Z	moderate	Biomarker	[20]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[21]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[22]
Intellectual disability	DISMBNXP	Limited	Biomarker	[18]
Melanoma	DIS1RRCY	Limited	Altered Expression	[23]
Stroke	DISX6UHX	Limited	Biomarker	[24]

14 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 Semaphorin-5A (SEMA5A).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Semaphorin-5A (SEMA5A).	[26]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Semaphorin-5A (SEMA5A).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Semaphorin-5A (SEMA5A).	[29]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Semaphorin-5A (SEMA5A).	[30]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Semaphorin-5A (SEMA5A).	[31]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Semaphorin-5A (SEMA5A).	[32]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Semaphorin-5A (SEMA5A).	[30]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Semaphorin-5A (SEMA5A).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Semaphorin-5A (SEMA5A).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Semaphorin-5A (SEMA5A).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Semaphorin-5A (SEMA5A).	[37]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Semaphorin-5A (SEMA5A).	[38]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Semaphorin-5A (SEMA5A).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Semaphorin-5A (SEMA5A).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Semaphorin-5A (SEMA5A).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Semaphorin-5A (SEMA5A).	[36]

References

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• [2] Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9.Pathol Oncol Res. 2013 Jan;19(1):11-8. doi: 10.1007/s12253-012-9550-8. Epub 2012 Jul 21.
• [3] A meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence.J Psychiatr Res. 2011 Nov;45(11):1419-25. doi: 10.1016/j.jpsychires.2011.06.005. Epub 2011 Jun 24.
• [4] Detecting genetic association through shortest paths in a bidirected graph.Genet Epidemiol. 2017 Sep;41(6):481-497. doi: 10.1002/gepi.22051. Epub 2017 Jun 19.
• [5] Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton.Oncogene. 2012 Feb 2;31(5):595-610. doi: 10.1038/onc.2011.256. Epub 2011 Jun 27.
• [6] FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits.Hum Mol Genet. 2019 Nov 15;28(22):3777-3791. doi: 10.1093/hmg/ddz217.
• [7] Elevated semaphorin5A in systemic lupus erythematosus is in association with disease activity and lupus nephritis.Clin Exp Immunol. 2017 May;188(2):234-242. doi: 10.1111/cei.12924. Epub 2017 Feb 17.
• [8] The association of semaphorin 5A with lymph node metastasis and adverse prognosis in cervical cancer.Cancer Cell Int. 2018 Jun 22;18:87. doi: 10.1186/s12935-018-0584-1. eCollection 2018.
• [9] A Combined ULBP2 and SEMA5A Expression Signature as a Prognostic and Predictive Biomarker for Colon Cancer.J Cancer. 2017 Apr 9;8(7):1113-1122. doi: 10.7150/jca.17872. eCollection 2017.
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• [12] Semaphorin 5A suppresses the proliferation and migration of lung adenocarcinoma cells.Int J Oncol. 2020 Jan;56(1):165-177. doi: 10.3892/ijo.2019.4932. Epub 2019 Dec 2.
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• [16] High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis.Int J Cancer. 2010 Sep 1;127(6):1373-83. doi: 10.1002/ijc.25166.
• [17] Meta analysis of the association of rs7702187 SNP in SEMA5A gene with risk of Parkinson's disease.Eur Rev Med Pharmacol Sci. 2014;18(6):900-4.
• [18] A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability.Eur J Hum Genet. 2016 Jun;24(6):838-43. doi: 10.1038/ejhg.2015.211. Epub 2015 Sep 23.
• [19] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [20] Multigenerational autosomal dominant inheritance of 5p chromosomal deletions.Am J Med Genet A. 2016 Mar;170(3):583-93. doi: 10.1002/ajmg.a.37445. Epub 2015 Nov 24.
• [21] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [22] High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma.Acta Haematol. 2020;143(3):279-288. doi: 10.1159/000502404. Epub 2019 Oct 9.
• [23] Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb.J Exp Clin Cancer Res. 2018 Nov 19;37(1):278. doi: 10.1186/s13046-018-0933-x.
• [24] Non-pulsed Sinusoidal Electromagnetic Field Rescues Animals From Severe Ischemic Stroke via NO Activation.Front Neurosci. 2019 Jun 19;13:561. doi: 10.3389/fnins.2019.00561. eCollection 2019.
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• [27] Editor's Highlight: Transcriptome Profiling Reveals Bisphenol A Alternatives Activate Estrogen Receptor Alpha in Human Breast Cancer Cells. Toxicol Sci. 2017 Aug 1;158(2):431-443. doi: 10.1093/toxsci/kfx101.
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• [31] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [32] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [35] 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.
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