Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT70YYWM)

DOT Name Homeobox protein SIX1 (SIX1)
Synonyms Sine oculis homeobox homolog 1
Gene Name SIX1
Related Disease
Adenocarcinoma ( )
Autosomal dominant nonsyndromic hearing loss 23 ( )
Branchio-oto-renal syndrome ( )
Branchiootic syndrome 1 ( )
Branchiootic syndrome 3 ( )
Glioma ( )
Rhabdomyosarcoma ( )
Acute myelogenous leukaemia ( )
Advanced cancer ( )
Bilateral renal agenesis ( )
Bone osteosarcoma ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Bronchiolitis obliterans syndrome ( )
Cervical Intraepithelial neoplasia ( )
Colorectal carcinoma ( )
Ear malformation ( )
Epithelial ovarian cancer ( )
Esophageal squamous cell carcinoma ( )
Glaucoma/ocular hypertension ( )
Hepatocellular carcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Open-angle glaucoma ( )
Osteosarcoma ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Prostate cancer ( )
Prostate carcinoma ( )
Sensorineural hearing loss disorder ( )
Wilms tumor ( )
Endometrial carcinoma ( )
Gastric cancer ( )
Metastatic malignant neoplasm ( )
Neuroblastoma ( )
Stomach cancer ( )
Autosomal dominant nonsyndromic hearing loss ( )
Branchiootic syndrome ( )
Endometrial cancer ( )
Non-small-cell lung cancer ( )
Cervical cancer ( )
Cervical carcinoma ( )
Endometrium neoplasm ( )
Melanoma ( )
Pancreatic cancer ( )
Type-1/2 diabetes ( )
UniProt ID
SIX1_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
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PDB ID
4EGC
Pfam ID
PF05920 ; PF16878
Sequence
MSMLPSFGFTQEQVACVCEVLQQGGNLERLGRFLWSLPACDHLHKNESVLKAKAVVAFHR
GNFRELYKILESHQFSPHNHPKLQQLWLKAHYVEAEKLRGRPLGAVGKYRVRRKFPLPRT
IWDGEETSYCFKEKSRGVLREWYAHNPYPSPREKRELAEATGLTTTQVSNWFKNRRQRDR
AAEAKERENTENNNSSSNKQNQLSPLEGGKPLMSSSEEEFSPPQSPDQNSVLLLQGNMGH
ARSSNYSLPGLTASQPSHGLQTHQHQLQDSLLGPLTSSLVDLGS
Function
Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as a transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5'-TCA[AG][AG]TTNC-3' motif present in the MEF3 element in the MYOG promoter and CIDEA enhancer. Regulates the expression of numerous genes, including MYC, CCND1 and EZR. Acts as an activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2. Regulates the expression of CCNA1. Promotes brown adipocyte differentiation.
Tissue Specificity Specifically expressed in skeletal muscle.
KEGG Pathway
Transcriptio.l misregulation in cancer (hsa05202 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adenocarcinoma DIS3IHTY Definitive Altered Expression [1]
Autosomal dominant nonsyndromic hearing loss 23 DISCMLYF Definitive Autosomal dominant [2]
Branchio-oto-renal syndrome DISIPQ53 Definitive Autosomal dominant [3]
Branchiootic syndrome 1 DISZ5BR7 Definitive GermlineCausalMutation [4]
Branchiootic syndrome 3 DIS62V4P Definitive Autosomal dominant [2]
Glioma DIS5RPEH Definitive Altered Expression [5]
Rhabdomyosarcoma DISNR7MS Definitive Biomarker [6]
Acute myelogenous leukaemia DISCSPTN Strong Biomarker [7]
Advanced cancer DISAT1Z9 Strong Altered Expression [8]
Bilateral renal agenesis DISOR5IA Strong Biomarker [9]
Bone osteosarcoma DIST1004 Strong Biomarker [10]
Breast cancer DIS7DPX1 Strong Biomarker [11]
Breast carcinoma DIS2UE88 Strong Biomarker [11]
Breast neoplasm DISNGJLM Strong Biomarker [12]
Bronchiolitis obliterans syndrome DISCK9IV Strong Biomarker [13]
Cervical Intraepithelial neoplasia DISXP757 Strong Altered Expression [14]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [15]
Ear malformation DISVJGPS Strong Genetic Variation [16]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [17]
Esophageal squamous cell carcinoma DIS5N2GV Strong Altered Expression [18]
Glaucoma/ocular hypertension DISLBXBY Strong Biomarker [19]
Hepatocellular carcinoma DIS0J828 Strong Altered Expression [11]
Lung cancer DISCM4YA Strong Altered Expression [20]
Lung carcinoma DISTR26C Strong Altered Expression [20]
Open-angle glaucoma DISSZEE8 Strong Biomarker [21]
Osteosarcoma DISLQ7E2 Strong Biomarker [10]
Ovarian cancer DISZJHAP Strong Biomarker [17]
Ovarian neoplasm DISEAFTY Strong Biomarker [17]
Prostate cancer DISF190Y Strong Posttranslational Modification [22]
Prostate carcinoma DISMJPLE Strong Posttranslational Modification [22]
Sensorineural hearing loss disorder DISJV45Z Strong Genetic Variation [16]
Wilms tumor DISB6T16 Strong Biomarker [23]
Endometrial carcinoma DISXR5CY moderate Altered Expression [24]
Gastric cancer DISXGOUK moderate Altered Expression [25]
Metastatic malignant neoplasm DIS86UK6 moderate Biomarker [26]
Neuroblastoma DISVZBI4 moderate Biomarker [27]
Stomach cancer DISKIJSX moderate Altered Expression [25]
Autosomal dominant nonsyndromic hearing loss DISYC1G0 Supportive Autosomal dominant [28]
Branchiootic syndrome DIS3X164 Supportive Autosomal dominant [4]
Endometrial cancer DISW0LMR Disputed Altered Expression [24]
Non-small-cell lung cancer DIS5Y6R9 Disputed Biomarker [29]
Cervical cancer DISFSHPF Limited Altered Expression [30]
Cervical carcinoma DIST4S00 Limited Altered Expression [30]
Endometrium neoplasm DIS6OS2L Limited Biomarker [31]
Melanoma DIS1RRCY Limited Altered Expression [32]
Pancreatic cancer DISJC981 Limited Biomarker [33]
Type-1/2 diabetes DISIUHAP Limited Altered Expression [34]
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⏷ Show the Full List of 47 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 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 Homeobox protein SIX1 (SIX1). [35]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Homeobox protein SIX1 (SIX1). [43]
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9 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 Homeobox protein SIX1 (SIX1). [36]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Homeobox protein SIX1 (SIX1). [37]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Homeobox protein SIX1 (SIX1). [38]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Homeobox protein SIX1 (SIX1). [39]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of Homeobox protein SIX1 (SIX1). [40]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Homeobox protein SIX1 (SIX1). [41]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of Homeobox protein SIX1 (SIX1). [42]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Homeobox protein SIX1 (SIX1). [44]
Lithium chloride DMHYLQ2 Investigative Lithium chloride increases the expression of Homeobox protein SIX1 (SIX1). [27]
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⏷ Show the Full List of 9 Drug(s)

References

1 Overexpression of SIX1 is an independent prognostic marker in stage I-III colorectal cancer.Int J Cancer. 2015 Nov 1;137(9):2104-13. doi: 10.1002/ijc.29596. Epub 2015 May 21.
2 A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred. Am J Hum Genet. 2000 Jun;66(6):1984-8. doi: 10.1086/302931. Epub 2000 Apr 24.
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 SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. doi: 10.1073/pnas.0308475101. Epub 2004 May 12.
5 EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma.Cell Physiol Biochem. 2018;49(5):1856-1869. doi: 10.1159/000493631. Epub 2018 Sep 19.
6 MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers.Oncogene. 2010 Sep 2;29(35):4971-9. doi: 10.1038/onc.2010.233. Epub 2010 Jul 5.
7 Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia.Cancer Sci. 2019 Jul;110(7):2200-2210. doi: 10.1111/cas.14033. Epub 2019 May 29.
8 Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network.Adv Cancer Res. 2019;141:1-42. doi: 10.1016/bs.acr.2018.12.001. Epub 2019 Jan 16.
9 SIX1 acts synergistically with TBX18 in mediating ureteral smooth muscle formation.Development. 2010 Mar;137(5):755-65. doi: 10.1242/dev.045757. Epub 2010 Jan 28.
10 miR?3b?p promotes the apoptosis and inhibits the proliferation and invasion of osteosarcoma cells by targeting SIX1.Mol Med Rep. 2018 Dec;18(6):5683-5692. doi: 10.3892/mmr.2018.9611. Epub 2018 Oct 30.
11 Six1 is negatively correlated with poor prognosis and reduces 5-fluorouracil sensitivity via attenuating the stemness of hepatocellular carcinoma cells.Eur J Pharmacol. 2019 Oct 15;861:172599. doi: 10.1016/j.ejphar.2019.172599. Epub 2019 Aug 9.
12 Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation.Cancer Res. 2008 Apr 1;68(7):2204-13. doi: 10.1158/0008-5472.CAN-07-3141.
13 Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchiootic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?.Mol Med Rep. 2018 Feb;17(2):3200-3205. doi: 10.3892/mmr.2017.8196. Epub 2017 Dec 6.
14 Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer.Int J Oncol. 2014 Sep;45(3):1232-40. doi: 10.3892/ijo.2014.2510. Epub 2014 Jun 20.
15 MicroRNA-362 Inhibits Cell Proliferation and Invasion by Directly Targeting SIX1 in Colorectal Cancer.Yonsei Med J. 2019 May;60(5):414-422. doi: 10.3349/ymj.2019.60.5.414.
16 A de novo SIX1 variant in a patient with a rare nonsyndromic cochleovestibular nerve abnormality, cochlear hypoplasia, and bilateral sensorineural hearing loss.Mol Genet Genomic Med. 2019 Dec;7(12):e995. doi: 10.1002/mgg3.995. Epub 2019 Oct 8.
17 Pro-survival effects by NF-B, Akt and ERK(1/2) and anti-apoptosis actions by Six1 disrupt apoptotic functions of TRAIL-Dr4/5 pathway in ovarian cancer.Biomed Pharmacother. 2016 Dec;84:1078-1087. doi: 10.1016/j.biopha.2016.10.028. Epub 2016 Oct 22.
18 SIX1 overexpression predicts poor prognosis and induces radioresistance through AKT signaling in esophageal squamous cell carcinoma.Onco Targets Ther. 2017 Feb 21;10:1071-1079. doi: 10.2147/OTT.S125330. eCollection 2017.
19 Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study.Sci Rep. 2017 Jun 29;7(1):4393. doi: 10.1038/s41598-017-02299-7.
20 MiR-150-5p regulates melanoma proliferation, invasion and metastasis via SIX1-mediated Warburg Effect.Biochem Biophys Res Commun. 2019 Jul 12;515(1):85-91. doi: 10.1016/j.bbrc.2019.05.111. Epub 2019 May 23.
21 Association of open-angle glaucoma loci with incident glaucoma in the Blue Mountains Eye Study.Am J Ophthalmol. 2015 Jan;159(1):31-6.e1. doi: 10.1016/j.ajo.2014.09.020. Epub 2014 Sep 19.
22 MicroRNA-30a functions as tumor suppressor and inhibits the proliferation and invasion of prostate cancer cells by down-regulation of SIX1.Hum Cell. 2017 Oct;30(4):290-299. doi: 10.1007/s13577-017-0170-1. Epub 2017 Jun 1.
23 A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.
24 MicroRNA-23a inhibits endometrial cancer cell development by targeting SIX1.Oncol Lett. 2019 Oct;18(4):3792-3802. doi: 10.3892/ol.2019.10694. Epub 2019 Jul 31.
25 SIX1 is upregulated in gastric cancer and regulates proliferation and invasion by targeting the ERK pathway and promoting epithelial-mesenchymal transition.Cell Biochem Funct. 2018 Dec;36(8):413-419. doi: 10.1002/cbf.3361. Epub 2018 Oct 31.
26 Dachshund 1 is Differentially Expressed Between Male and Female Breast Cancer: A Matched Case-Control Study of Clinical Characteristics and Prognosis.Clin Breast Cancer. 2018 Oct;18(5):e875-e882. doi: 10.1016/j.clbc.2018.01.011. Epub 2018 Feb 2.
27 The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
28 Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
29 miR-186-5p targeting SIX1 inhibits cisplatin resistance in non-small-cell lung cancer cells (NSCLCs).Neoplasma. 2020 Jan;67(1):147-157. doi: 10.4149/neo_2019_190511N420. Epub 2019 Nov 4.
30 HPV16-transformed human keratinocytes depend on SIX1 expression for proliferation and HPV E6/E7 gene expression.Virology. 2019 Nov;537:20-30. doi: 10.1016/j.virol.2019.08.009. Epub 2019 Aug 13.
31 SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.Mol Cancer Res. 2016 Sep;14(9):849-58. doi: 10.1158/1541-7786.MCR-16-0084. Epub 2016 Jun 3.
32 Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma.Mol Oncol. 2019 Jun;13(6):1433-1449. doi: 10.1002/1878-0261.12501. Epub 2019 May 25.
33 Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer.BMC Cancer. 2017 Apr 7;17(1):249. doi: 10.1186/s12885-017-3225-5.
34 Gas1 expression in parietal cells of Bowman's capsule in experimental diabetic nephropathy.Histochem Cell Biol. 2017 Jul;148(1):33-47. doi: 10.1007/s00418-017-1550-z. Epub 2017 Mar 18.
35 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
36 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
37 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.
38 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.
39 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.
40 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
41 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
42 Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
43 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.
44 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.
45 The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.