Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9H4WWE)

• DOT Name: Transcription factor SOX-17 (SOX17)
• Gene Name: SOX17
• Related Disease:
  Asthma
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Pulmonary arterial hypertension
  Vesicoureteral reflux 3
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adenoma
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Cervical cancer
  Cervical carcinoma
  Cholangiocarcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Endometrial carcinoma
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Heritable pulmonary arterial hypertension
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Retinoblastoma
  Seminoma
  Stomach cancer
  Colon cancer
  Colon carcinoma
  Gastric neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Vesicoureteral reflux
  Familial vesicoureteral reflux
  Breast neoplasm
  Endometrial cancer
  Metastatic malignant neoplasm
  Squamous cell carcinoma
• UniProt ID: SOX17_HUMAN
• PDB ID: 2YUL; 4A3N
• Pfam ID: PF00505 ; PF12067
• Sequence:
  MSSPDAGYASDDQSQTQSALPAVMAGLGPCPWAESLSPIGDMKVKGEAPANSGAPAGAAG
  RAKGESRIRRPMNAFMVWAKDERKRLAQQNPDLHNAELSKMLGKSWKALTLAEKRPFVEE
  AERLRVQHMQDHPNYKYRPRRRKQVKRLKRVEGGFLHGLAEPQAAALGPEGGRVAMDGLG
  LQFPEQGFPAGPPLLPPHMGGHYRDCQSLGAPPLDGYPLPTPDTSPLDGVDPDPAFFAAP
  MPGDCPAAGTYSYAQVSDYAGPPEPPAGPMHPRLGPEPAGPSIPGLLAPPSALHVYYGAM
  GSPGAGGGRGFQMQPQHQHQHQHQHHPPGPGQPSPPPEALPCRDGTDPSQPAELLGEVDR
  TEFEQYLHFVCKPEMGLPYQGHDSGVNLPDSHGAISSVVSDASSAVYYCNYPDV
• Function: Acts as a transcription regulator that binds target promoter DNA and bends the DNA. Binds to the sequences 5'-AACAAT-'3 or 5'-AACAAAG-3'. Modulates transcriptional regulation via WNT3A. Inhibits Wnt signaling. Promotes degradation of activated CTNNB1. Plays a key role in the regulation of embryonic development. Required for normal development of the definitive gut endoderm. Required for normal looping of the embryonic heart tube. Plays an important role in embryonic and postnatal vascular development, including development of arteries. Plays an important role in postnatal angiogenesis, where it is functionally redundant with SOX18. Required for the generation and maintenance of fetal hematopoietic stem cells, and for fetal hematopoiesis. Probable transcriptional activator in the premeiotic germ cells.
• Tissue Specificity: Expressed in adult heart, lung, spleen, testis, ovary, placenta, fetal lung, and kidney. In normal gastrointestinal tract, it is preferentially expressed in esophagus, stomach and small intestine than in colon and rectum.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  Formation of definitive endoderm (R-HSA-9823730)
  Specification of primordial germ cells (R-HSA-9827857)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[2]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[2]
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[3]
Vesicoureteral reflux 3	DIS4YKU8	Definitive	Autosomal dominant	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[5]
Adenocarcinoma	DIS3IHTY	Strong	Posttranslational Modification	[6]
Adenoma	DIS78ZEV	Strong	Biomarker	[7]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[8]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[10]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[11]
Cervical cancer	DISFSHPF	Strong	Biomarker	[12]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[14]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[15]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[16]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[17]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[18]
Heritable pulmonary arterial hypertension	DISD1Y94	Strong	Biomarker	[19]
Lung cancer	DISCM4YA	Strong	Altered Expression	[20]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[20]
Neoplasm	DISZKGEW	Strong	Altered Expression	[21]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[22]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[23]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[24]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[17]
Colon cancer	DISVC52G	moderate	Biomarker	[25]
Colon carcinoma	DISJYKUO	moderate	Altered Expression	[25]
Gastric neoplasm	DISOKN4Y	moderate	Biomarker	[25]
Thyroid cancer	DIS3VLDH	moderate	Posttranslational Modification	[26]
Thyroid gland carcinoma	DISMNGZ0	moderate	Posttranslational Modification	[26]
Thyroid gland papillary carcinoma	DIS48YMM	moderate	Altered Expression	[26]
Thyroid tumor	DISLVKMD	moderate	Posttranslational Modification	[26]
Vesicoureteral reflux	DISUL6SA	moderate	Genetic Variation	[4]
Familial vesicoureteral reflux	DISUME5E	Supportive	Autosomal dominant	[4]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[27]
Endometrial cancer	DISW0LMR	Limited	Biomarker	[28]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[29]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[30]

12 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 Transcription factor SOX-17 (SOX17).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor SOX-17 (SOX17).	[33]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor SOX-17 (SOX17).	[34]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor SOX-17 (SOX17).	[35]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Transcription factor SOX-17 (SOX17).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transcription factor SOX-17 (SOX17).	[37]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Transcription factor SOX-17 (SOX17).	[38]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Transcription factor SOX-17 (SOX17).	[39]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transcription factor SOX-17 (SOX17).	[39]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Transcription factor SOX-17 (SOX17).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcription factor SOX-17 (SOX17).	[43]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Transcription factor SOX-17 (SOX17).	[44]

16 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Imatinib	DM7RJXL	Approved	Imatinib decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Vandetanib	DMRICNP	Approved	Vandetanib decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Ziprasidone	DMM58JY	Approved	Ziprasidone decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Ritanserin	DM0X36Y	Discontinued in Phase 3	Ritanserin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
SB-431542	DM0YOXQ	Preclinical	SB-431542 decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the localization of Transcription factor SOX-17 (SOX17).	[32]
BROMODEOXYURIDINE	DM0D7LA	Investigative	BROMODEOXYURIDINE decreases the localization of Transcription factor SOX-17 (SOX17).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of Transcription factor SOX-17 (SOX17).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor SOX-17 (SOX17).	[41]

References

• [1] Endothelial Sox17 promotes allergic airway inflammation.J Allergy Clin Immunol. 2019 Aug;144(2):561-573.e6. doi: 10.1016/j.jaci.2019.02.034. Epub 2019 Mar 28.
• [2] Screening the molecular targets of ovarian cancer based on bioinformatics analysis.Tumori. 2015 Jul-Aug;101(4):384-9. doi: 10.5301/tj.5000319. Epub 2015 Jul 2.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. Hum Mutat. 2010 Dec;31(12):1352-9. doi: 10.1002/humu.21378. Epub 2010 Nov 9.
• [5] Low SOX17 expression: prognostic significance in de novo acute myeloid leukemia with normal cytogenetics.Clin Chem Lab Med. 2014 Dec;52(12):1843-50. doi: 10.1515/cclm-2014-0487.
• [6] SOX17 expression and its down-regulation by promoter methylation in cervical adenocarcinoma in situ and adenocarcinoma.Histopathology. 2020 Feb;76(3):383-393. doi: 10.1111/his.13980. Epub 2019 Dec 1.
• [7] Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists.BMC Cancer. 2014 Nov 29;14:891. doi: 10.1186/1471-2407-14-891.
• [8] Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice.J Clin Invest. 2013 Jan;123(1):418-31. doi: 10.1172/JCI64547. Epub 2012 Dec 17.
• [9] 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.
• [10] Knockdown of miR-194-5p inhibits cell proliferation, migration and invasion in breast cancer by regulating the Wnt/-catenin signaling pathway.Int J Mol Med. 2018 Dec;42(6):3355-3363. doi: 10.3892/ijmm.2018.3897. Epub 2018 Sep 25.
• [11] SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.J Biomed Sci. 2019 Feb 18;26(1):20. doi: 10.1186/s12929-019-0510-4.
• [12] Performance of a DNA methylation marker panel using liquid-based cervical scrapes to detect cervical cancer and its precancerous stages.BMC Cancer. 2018 Dec 3;18(1):1197. doi: 10.1186/s12885-018-5125-8.
• [13] SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma.J Hepatol. 2017 Jul;67(1):72-83. doi: 10.1016/j.jhep.2017.02.017. Epub 2017 Feb 22.
• [14] SOX17 antagonizes WNT/-catenin signaling pathway in hepatocellular carcinoma.Epigenetics. 2010 Nov-Dec;5(8):743-9. doi: 10.4161/epi.5.8.13104. Epub 2010 Nov 22.
• [15] Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res. 2008 Apr 15;68(8):2764-72. doi: 10.1158/0008-5472.CAN-07-6349.
• [16] SOX17, -catenin and CyclinD1 expression in the endometrioid adenocarcinoma and influence of 5-AZA on expression.Cancer Gene Ther. 2020 Apr;27(3-4):256-263. doi: 10.1038/s41417-019-0135-5. Epub 2019 Sep 23.
• [17] Assessment of SOX17 DNA methylation in cell free DNA from patients with operable gastric cancer. Association with prognostic variables and survival.Clin Chem Lab Med. 2013 Jul;51(7):1505-10. doi: 10.1515/cclm-2012-0320.
• [18] Sox17 inhibits hepatocellular carcinoma progression by downregulation of KIF14 expression.Tumour Biol. 2014 Nov;35(11):11199-207. doi: 10.1007/s13277-014-2398-7. Epub 2014 Aug 10.
• [19] SOX17 Mutations in Japanese Patients with Pulmonary Arterial Hypertension.Am J Respir Crit Care Med. 2018 Nov 1;198(9):1231-1233. doi: 10.1164/rccm.201804-0766LE.
• [20] SOX17 methylation inhibits its antagonism of Wnt signaling pathway in lung cancer.Discov Med. 2012 Jul;14(74):33-40.
• [21] Lentiviral-Mediated Overexpression of MicroRNA-141 Promotes Cell Proliferation and Inhibits Apoptosis in Human Esophageal Squamous Cell Carcinoma.Recent Pat Anticancer Drug Discov. 2019;14(2):170-176. doi: 10.2174/1574892814666181231142136.
• [22] SOX17 promoter methylation in plasma circulating tumor DNA of patients with non-small cell lung cancer.Clin Chem Lab Med. 2016 Aug 1;54(8):1385-93. doi: 10.1515/cclm-2015-0776.
• [23] The effect of miR-340 over-expression on cell-cycle-related genes in triple-negative breast cancer cells.Eur J Cancer Care (Engl). 2017 Nov;26(6). doi: 10.1111/ecc.12496. Epub 2016 May 27.
• [24] Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumor fate.Int J Cancer. 2020 Mar 15;146(6):1592-1605. doi: 10.1002/ijc.32714. Epub 2019 Nov 1.
• [25] Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis.Gastroenterology. 2009 Oct;137(4):1346-57. doi: 10.1053/j.gastro.2009.06.041. Epub 2009 Jun 21.
• [26] Epigenetic regulation of Wnt signaling pathway gene SRY-related HMG-box 17 in papillary thyroid carcinoma.Chin Med J (Engl). 2012 Oct;125(19):3526-31.
• [27] Development and validation of a multiplex methylation specific PCR-coupled liquid bead array for liquid biopsy analysis.Clin Chim Acta. 2016 Oct 1;461:156-64. doi: 10.1016/j.cca.2016.08.003. Epub 2016 Aug 7.
• [28] SOX17 in cellular reprogramming and cancer.Semin Cancer Biol. 2020 Dec;67(Pt 1):65-73. doi: 10.1016/j.semcancer.2019.08.008. Epub 2019 Aug 13.
• [29] SOX17 Inhibits Tumor Metastasis Via Wnt Signaling In Endometrial Cancer.Onco Targets Ther. 2019 Oct 7;12:8275-8286. doi: 10.2147/OTT.S220536. eCollection 2019.
• [30] Aberrantly hypermethylated tumor suppressor genes were identified in oral squamous cell carcinoma (OSCC).Clin Epigenetics. 2019 Aug 12;11(1):116. doi: 10.1186/s13148-019-0715-0.
• [31] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [32] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [33] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [34] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [35] 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.
• [36] Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res. 2008 Apr 15;68(8):2764-72. doi: 10.1158/0008-5472.CAN-07-6349.
• [37] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [38] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [39] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [40] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [41] 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.
• [42] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [43] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [44] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.