Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8MKEU)

• DOT Name: Slit homolog 3 protein (SLIT3)
• Synonyms: Slit-3; Multiple epidermal growth factor-like domains protein 5; Multiple EGF-like domains protein 5
• Gene Name: SLIT3
• Related Disease:
  Alzheimer disease
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colorectal adenoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Endometriosis
  Endometrium adenocarcinoma
  Epithelial ovarian cancer
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  MASS syndrome
  Melanoma
  Metabolic bone disease
  Neoplasm
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Postmenopausal osteoporosis
  Schizophrenia
  Stomach cancer
  Familial atrial fibrillation
  Lung adenocarcinoma
  Squamous cell carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Congenital diaphragmatic hernia
  Hepatocellular carcinoma
  Periodontal disease
  Periodontitis
  Psoriasis
  Rheumatoid arthritis
• UniProt ID: SLIT3_HUMAN
• Pfam ID: PF00008 ; PF12661 ; PF02210 ; PF13855 ; PF01463 ; PF01462
• Sequence:
  MAPGWAGVGAAVRARLALALALASVLSGPPAVACPTKCTCSAASVDCHGLGLRAVPRGIP
  RNAERLDLDRNNITRITKMDFAGLKNLRVLHLEDNQVSVIERGAFQDLKQLERLRLNKNK
  LQVLPELLFQSTPKLTRLDLSENQIQGIPRKAFRGITDVKNLQLDNNHISCIEDGAFRAL
  RDLEILTLNNNNISRILVTSFNHMPKIRTLRLHSNHLYCDCHLAWLSDWLRQRRTVGQFT
  LCMAPVHLRGFNVADVQKKEYVCPAPHSEPPSCNANSISCPSPCTCSNNIVDCRGKGLME
  IPANLPEGIVEIRLEQNSIKAIPAGAFTQYKKLKRIDISKNQISDIAPDAFQGLKSLTSL
  VLYGNKITEIVKGLFDGLVSLQLLLLNANKINCLRVNTFQDLQNLNLLSLYDNKLQTISK
  GLFAPLQSIQTLHLAQNPFVCDCHLKWLADYLQDNPIETSGARCSSPRRLANKRISQIKS
  KKFRCSGSEDYRSRFSSECFMDLVCPEKCRCEGTIVDCSNQKLVRIPSHLPEYVTDLRLN
  DNEVSVLEATGIFKKLPNLRKINLSNNKIKEVREGAFDGAASVQELMLTGNQLETVHGRV
  FRGLSGLKTLMLRSNLIGCVSNDTFAGLSSVRLLSLYDNRITTITPGAFTTLVSLSTINL
  LSNPFNCNCHLAWLGKWLRKRRIVSGNPRCQKPFFLKEIPIQDVAIQDFTCDGNEESSCQ
  LSPRCPEQCTCMETVVRCSNKGLRALPRGMPKDVTELYLEGNHLTAVPRELSALRHLTLI
  DLSNNSISMLTNYTFSNMSHLSTLILSYNRLRCIPVHAFNGLRSLRVLTLHGNDISSVPE
  GSFNDLTSLSHLALGTNPLHCDCSLRWLSEWVKAGYKEPGIARCSSPEPMADRLLLTTPT
  HRFQCKGPVDINIVAKCNACLSSPCKNNGTCTQDPVELYRCACPYSYKGKDCTVPINTCI
  QNPCQHGGTCHLSDSHKDGFSCSCPLGFEGQRCEINPDDCEDNDCENNATCVDGINNYVC
  ICPPNYTGELCDEVIDHCVPELNLCQHEAKCIPLDKGFSCECVPGYSGKLCETDNDDCVA
  HKCRHGAQCVDTINGYTCTCPQGFSGPFCEHPPPMVLLQTSPCDQYECQNGAQCIVVQQE
  PTCRCPPGFAGPRCEKLITVNFVGKDSYVELASAKVRPQANISLQVATDKDNGILLYKGD
  NDPLALELYQGHVRLVYDSLSSPPTTVYSVETVNDGQFHSVELVTLNQTLNLVVDKGTPK
  SLGKLQKQPAVGINSPLYLGGIPTSTGLSALRQGTDRPLGGFHGCIHEVRINNELQDFKA
  LPPQSLGVSPGCKSCTVCKHGLCRSVEKDSVVCECRPGWTGPLCDQEARDPCLGHRCHHG
  KCVATGTSYMCKCAEGYGGDLCDNKNDSANACSAFKCHHGQCHISDQGEPYCLCQPGFSG
  EHCQQENPCLGQVVREVIRRQKGYASCATASKVPIMECRGGCGPQCCQPTRSKRRKYVFQ
  CTDGSSFVEEVERHLECGCLACS
• Function: May act as molecular guidance cue in cellular migration, and function may be mediated by interaction with roundabout homolog receptors.
• Tissue Specificity: Predominantly expressed in thyroid.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  Signaling by ROBO receptors (R-HSA-376176)
  Regulation of commissural axon pathfinding by SLIT and ROBO (R-HSA-428542)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal adenoma	DISTSVHM	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[6]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[7]
Endometriosis	DISX1AG8	Strong	Biomarker	[8]
Endometrium adenocarcinoma	DISY6744	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[12]
MASS syndrome	DISI3721	Strong	Genetic Variation	[13]
Melanoma	DIS1RRCY	Strong	Altered Expression	[14]
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Osteoporosis	DISF2JE0	Strong	Biomarker	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[13]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[18]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[11]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[19]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[20]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[20]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[20]
Congenital diaphragmatic hernia	DIS0IPVU	Limited	Biomarker	[21]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[16]
Periodontal disease	DISJQHVN	Limited	Biomarker	[22]
Periodontitis	DISI9JOI	Limited	Biomarker	[22]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[23]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[24]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Slit homolog 3 protein (SLIT3) affects the response to substance of Daunorubicin.	[40]
Nitazoxanide	DMOWLVG	Approved	Slit homolog 3 protein (SLIT3) affects the response to substance of Nitazoxanide.	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Slit homolog 3 protein (SLIT3).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Slit homolog 3 protein (SLIT3).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Slit homolog 3 protein (SLIT3).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Slit homolog 3 protein (SLIT3).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Slit homolog 3 protein (SLIT3).	[30]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Slit homolog 3 protein (SLIT3).	[31]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Slit homolog 3 protein (SLIT3).	[32]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Slit homolog 3 protein (SLIT3).	[33]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Slit homolog 3 protein (SLIT3).	[34]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Slit homolog 3 protein (SLIT3).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Slit homolog 3 protein (SLIT3).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Slit homolog 3 protein (SLIT3).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Slit homolog 3 protein (SLIT3).	[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 Slit homolog 3 protein (SLIT3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Slit homolog 3 protein (SLIT3).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Slit homolog 3 protein (SLIT3).	[37]

References

• [1] Increased permeability of the blood-brain barrier and Alzheimer's disease-like alterations in slit-2 transgenic mice.J Alzheimers Dis. 2015;43(2):535-48. doi: 10.3233/JAD-141215.
• [2] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [3] Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers.Br J Cancer. 2004 Dec 13;91(12):2071-8. doi: 10.1038/sj.bjc.6602222.
• [4] SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium.Cancer Res. 2008 Oct 1;68(19):7819-27. doi: 10.1158/0008-5472.CAN-08-1357.
• [5] A gene expression and pre-mRNA splicing signature that marks the adenoma-adenocarcinoma progression in colorectal cancer.PLoS One. 2014 Feb 6;9(2):e87761. doi: 10.1371/journal.pone.0087761. eCollection 2014.
• [6] MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer.Oncotarget. 2016 Aug 16;7(33):53443-53458. doi: 10.18632/oncotarget.10803.
• [7] Curcumin exhibits anti-tumor effect and attenuates cellular migration via Slit-2 mediated down-regulation of SDF-1 and CXCR4 in endometrial adenocarcinoma cells.J Nutr Biochem. 2017 Jun;44:60-70. doi: 10.1016/j.jnutbio.2016.12.021. Epub 2017 Mar 16.
• [8] The Expression and Cellular Localisation of Neurotrophin and Neural Guidance Molecules in Peritoneal Ectopic Lesions.Mol Neurobiol. 2019 Jun;56(6):4013-4022. doi: 10.1007/s12035-018-1348-6. Epub 2018 Sep 25.
• [9] Bioinformatics analysis to screen the key prognostic genes in ovarian cancer.J Ovarian Res. 2017 Apr 13;10(1):27. doi: 10.1186/s13048-017-0323-6.
• [10] MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor.PLoS Genet. 2010 Mar 12;6(3):e1000879. doi: 10.1371/journal.pgen.1000879.
• [11] Effects of Slit3 silencing on the invasive ability of lung carcinoma A549 cells.Oncol Rep. 2015 Aug;34(2):952-60. doi: 10.3892/or.2015.4031. Epub 2015 Jun 5.
• [12] Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder.PLoS One. 2010 Dec 1;5(12):e15463. doi: 10.1371/journal.pone.0015463.
• [13] Targeting skeletal endothelium to ameliorate bone loss.Nat Med. 2018 Jun;24(6):823-833. doi: 10.1038/s41591-018-0020-z. Epub 2018 May 21.
• [14] Slit3 inhibits activator protein 1-mediated migration of malignant melanoma cells.Int J Mol Med. 2011 Nov;28(5):721-6. doi: 10.3892/ijmm.2011.742. Epub 2011 Jul 8.
• [15] Osteoclast-secreted SLIT3 coordinates bone resorption and formation.J Clin Invest. 2018 Apr 2;128(4):1429-1441. doi: 10.1172/JCI91086. Epub 2018 Mar 5.
• [16] Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3/-catenin pathway.BMC Cancer. 2018 Jun 1;18(1):621. doi: 10.1186/s12885-018-4326-5.
• [17] Opening windows for bone remodeling through a SLIT.J Clin Invest. 2018 Apr 2;128(4):1255-1257. doi: 10.1172/JCI120325. Epub 2018 Mar 5.
• [18] Genetic structure adds power to detect schizophrenia susceptibility at SLIT3 in the Chinese Han population.Genome Res. 2004 Jul;14(7):1345-9. doi: 10.1101/gr.1758204.
• [19] Slit-2 facilitates interaction of P-cadherin with Robo-3 and inhibits cell migration in an oral squamous cell carcinoma cell line.Carcinogenesis. 2011 Jun;32(6):935-43. doi: 10.1093/carcin/bgr059. Epub 2011 Mar 31.
• [20] Down-regulation of miR-218-2 and its host gene SLIT3 cooperate to promote invasion and progression of thyroid cancer.J Clin Endocrinol Metab. 2013 Aug;98(8):E1334-44. doi: 10.1210/jc.2013-1053. Epub 2013 May 29.
• [21] Echocardiography allows for analysis of pulmonary arterial flow in mice with congenital diaphragmatic hernia.J Surg Res. 2018 Jan;221:35-42. doi: 10.1016/j.jss.2017.06.080.
• [22] Gingival crevicular fluid levels of SLIT3 are increased in periodontal disease.Oral Dis. 2020 Jan;26(1):182-192. doi: 10.1111/odi.13227. Epub 2019 Nov 26.
• [23] Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.Am J Hum Genet. 2015 Jan 8;96(1):104-20. doi: 10.1016/j.ajhg.2014.12.004.
• [24] Slit3 inhibits Robo3-induced invasion of synovial fibroblasts in rheumatoid arthritis.Arthritis Res Ther. 2010;12(2):R45. doi: 10.1186/ar2955. Epub 2010 Mar 18.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] 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.
• [27] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [28] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [29] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [30] 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.
• [31] 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.
• [32] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [33] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [34] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [35] 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.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [40] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.
• [41] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.