Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor SOX-18 (SOX18)
• Gene Name: SOX18
• Related Disease:
  Kidney failure
  Acute myelogenous leukaemia
  Adenocarcinoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Endometrial cancer
  Endometrial carcinoma
  Epileptic encephalopathy
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Hypotrichosis
  Hypotrichosis-lymphedema-telangiectasia syndrome
  Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Skin disease
  X-linked Opitz G/BBB syndrome
  Bladder cancer
  High blood pressure
  Lymphatic malformation 1
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hypotrichosis-lymphedema-telangiectasia syndrome (grouping)
  Mycosis fungoides
  Capillary hemangioma
  Clear cell renal carcinoma
  Hemangioma
  Invasive ductal breast carcinoma
  Metastatic malignant neoplasm
  Pancreatic ductal carcinoma
  Vascular disease
• UniProt ID: SOX18_HUMAN
• Pfam ID: PF00505 ; PF12067
• Sequence:
  MQRSPPGYGAQDDPPARRDCAWAPGHGAAADTRGLAAGPAALAAPAAPASPPSPQRSPPR
  SPEPGRYGLSPAGRGERQAADESRIRRPMNAFMVWAKDERKRLAQQNPDLHNAVLSKMLG
  KAWKELNAAEKRPFVEEAERLRVQHLRDHPNYKYRPRRKKQARKARRLEPGLLLPGLAPP
  QPPPEPFPAASGSARAFRELPPLGAEFDGLGLPTPERSPLDGLEPGEAAFFPPPAAPEDC
  ALRPFRAPYAPTELSRDPGGCYGAPLAEALRTAPPAAPLAGLYYGTLGTPGPYPGPLSPP
  PEAPPLESAEPLGPAADLWADVDLTEFDQYLNCSRTRPDAPGLPYHVALAKLGPRAMSCP
  EESSLISALSDASSAVYYSACISG
• Function: Transcriptional activator that binds to the consensus sequence 5'-AACAAAG-3' in the promoter of target genes and plays an essential role in embryonic cardiovascular development and lymphangiogenesis. Activates transcription of PROX1 and other genes coding for lymphatic endothelial markers. Plays an essential role in triggering the differentiation of lymph vessels, but is not required for the maintenance of differentiated lymphatic endothelial cells. Plays an important role in postnatal angiogenesis, where it is functionally redundant with SOX17. Interaction with MEF2C enhances transcriptional activation. Besides, required for normal hair development.
• Tissue Specificity: Detected in heart, lung, placenta, skeletal muscle, liver, kidney, spleen, prostate, ovary, msosmall intestine and colon.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kidney failure	DISOVQ9P	Definitive	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[9]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[10]
Epileptic encephalopathy	DISZOCA3	Strong	Altered Expression	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hypotrichosis	DISSW933	Strong	Genetic Variation	[14]
Hypotrichosis-lymphedema-telangiectasia syndrome	DIS2C8IX	Strong	Autosomal recessive	[15]
Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome	DISPABDF	Strong	Autosomal dominant	[15]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[17]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[12]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Altered Expression	[18]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[18]
Skin disease	DISDW8R6	Strong	Biomarker	[19]
X-linked Opitz G/BBB syndrome	DISQ14EC	Strong	Altered Expression	[11]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[20]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[21]
Lymphatic malformation 1	DIS857QZ	moderate	Genetic Variation	[14]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[20]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[20]
Hypotrichosis-lymphedema-telangiectasia syndrome (grouping)	DISTB4GU	Supportive	Autosomal dominant	[1]
Mycosis fungoides	DIS62RB8	Disputed	Biomarker	[22]
Capillary hemangioma	DISQ8XPT	Limited	Biomarker	[23]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[24]
Hemangioma	DISDCGAG	Limited	Genetic Variation	[23]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[12]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[23]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[25]
Vascular disease	DISVS67S	Limited	Biomarker	[23]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Transcription factor SOX-18 (SOX18) affects the response to substance of Fluorouracil.	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcription factor SOX-18 (SOX18).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor SOX-18 (SOX18).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Transcription factor SOX-18 (SOX18).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor SOX-18 (SOX18).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Transcription factor SOX-18 (SOX18).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription factor SOX-18 (SOX18).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor SOX-18 (SOX18).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Transcription factor SOX-18 (SOX18).	[32]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor SOX-18 (SOX18).	[33]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Transcription factor SOX-18 (SOX18).	[28]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Transcription factor SOX-18 (SOX18).	[34]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Transcription factor SOX-18 (SOX18).	[35]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor SOX-18 (SOX18).	[36]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Transcription factor SOX-18 (SOX18).	[38]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Transcription factor SOX-18 (SOX18).	[40]

2 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 Transcription factor SOX-18 (SOX18).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription factor SOX-18 (SOX18).	[39]

References

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• [2] Prognostic significance of SOX2, SOX3, SOX11, SOX14 and SOX18 gene expression in adult de novo acute myeloid leukemia.Leuk Res. 2018 Apr;67:32-38. doi: 10.1016/j.leukres.2018.02.001. Epub 2018 Feb 6.
• [3] Influence of miR-7a and miR-24-3p on the SOX18 transcript in lung adenocarcinoma.Oncol Rep. 2018 Jan;39(1):201-208. doi: 10.3892/or.2017.6077. Epub 2017 Nov 6.
• [4] The role of SOX family members in solid tumours and metastasis.Semin Cancer Biol. 2020 Dec;67(Pt 1):122-153. doi: 10.1016/j.semcancer.2019.03.004. Epub 2019 Mar 23.
• [5] MicroRNAs modulate the expression of the SOX18 transcript in lung squamous cell carcinoma.Oncol Rep. 2016 Nov;36(5):2884-2892. doi: 10.3892/or.2016.5102. Epub 2016 Sep 19.
• [6] Interleukin-6 upregulates SOX18 expression in osteosarcoma.Onco Targets Ther. 2017 Nov 8;10:5329-5336. doi: 10.2147/OTT.S149905. eCollection 2017.
• [7] Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.Elife. 2017 Jan 31;6:e21221. doi: 10.7554/eLife.21221.
• [8] Upregulation of SOX18 in colorectal cancer cells promotes proliferation and correlates with colorectal cancer risk.Onco Targets Ther. 2018 Nov 29;11:8481-8490. doi: 10.2147/OTT.S178916. eCollection 2018.
• [9] Impact of SOX18 expression in cancer cells and vessels on the outcome of invasive ductal breast carcinoma.Cell Oncol (Dordr). 2013 Dec;36(6):469-83. doi: 10.1007/s13402-013-0151-7. Epub 2013 Sep 25.
• [10] SOX11 hypermethylation as a tumor biomarker in endometrial cancer.Biochimie. 2019 Jul;162:8-14. doi: 10.1016/j.biochi.2019.03.019. Epub 2019 Mar 29.
• [11] Heterogeneous expression and biological function of SOX18 in osteosaroma.J Cell Biochem. 2018 May;119(5):4184-4192. doi: 10.1002/jcb.26635. Epub 2018 Jan 22.
• [12] SOX18 Affects Cell Viability, Migration, Invasiveness, and Apoptosis in Hepatocellular Carcinoma (HCC) Cells by Participating in Epithelial-to-Mesenchymal Transition (EMT) Progression and Adenosine Monophosphate Activated Protein Kinase (AMPK)/Mammalian Target of Rapamycin (mTOR).Med Sci Monit. 2019 Aug 20;25:6244-6254. doi: 10.12659/MSM.915729.
• [13] Fibroblast Growth Factor 19-Mediated Up-regulation of SYR-Related High-Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms-Related Tyrosine Kinase 4.Hepatology. 2020 May;71(5):1712-1731. doi: 10.1002/hep.30951. Epub 2020 Feb 10.
• [14] Further delineation of the SOX18-related Hypotrichosis, Lymphedema, Telangiectasia syndrome (HTLS).Eur J Med Genet. 2018 May;61(5):269-272. doi: 10.1016/j.ejmg.2018.01.001. Epub 2018 Jan 4.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] Effect of disrupted SOX18 transcription factor function on tumor growth, vascularization, and endothelial development.J Natl Cancer Inst. 2006 Aug 2;98(15):1060-7. doi: 10.1093/jnci/djj299.
• [17] Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis.Nat Commun. 2019 Jan 3;10(1):18. doi: 10.1038/s41467-018-07961-w.
• [18] Overexpression of SOX18 promotes prostate cancer progression via the regulation of TCF1, c-Myc, cyclinD1 and MMP-7.Oncol Rep. 2017 Feb;37(2):1045-1051. doi: 10.3892/or.2016.5288. Epub 2016 Dec 2.
• [19] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [20] The role of SOX18 in bladder cancer and its underlying mechanism in mediating cellular functions.Life Sci. 2019 Sep 1;232:116614. doi: 10.1016/j.lfs.2019.116614. Epub 2019 Jun 28.
• [21] A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis-lymphedema-telangiectasia syndrome.Am J Med Genet A. 2018 Dec;176(12):2824-2828. doi: 10.1002/ajmg.a.40532. Epub 2018 Dec 14.
• [22] Expression of SOX18 in Mycosis Fungoides.Acta Derm Venereol. 2017 Jan 4;97(1):17-23. doi: 10.2340/00015555-2466.
• [23] R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma.Elife. 2019 Jul 30;8:e43026. doi: 10.7554/eLife.43026.
• [24] Transcription Factor SOX18 Promotes Clear Cell Renal Cell Carcinoma Progression and Alleviates Cabozantinib-Mediated Inhibitory Effects.Mol Cancer Ther. 2019 Dec;18(12):2433-2445. doi: 10.1158/1535-7163.MCT-19-0043. Epub 2019 Sep 16.
• [25] MiR-7-5p functions as a tumor suppressor by targeting SOX18 in pancreatic ductal adenocarcinoma.Biochem Biophys Res Commun. 2018 Mar 18;497(4):963-970. doi: 10.1016/j.bbrc.2018.02.005. Epub 2018 Mar 1.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [28] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [29] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [30] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [31] 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.
• [32] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [33] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [34] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [35] 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.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] 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.
• [38] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [39] 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.
• [40] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [41] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.