Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP5E3VU)

• DOT Name: Homeobox protein SIX3 (SIX3)
• Synonyms: Sine oculis homeobox homolog 3
• Gene Name: SIX3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Chondrosarcoma
  Holoprosencephaly 2
  Holoprosencephaly 5
  Non-insulin dependent diabetes
  Adult glioblastoma
  Alobar holoprosencephaly
  Astrocytoma
  Carcinoma of esophagus
  Cytomegalovirus infection
  Esophageal cancer
  Glioblastoma multiforme
  Glioma
  Hypopituitarism
  Kallmann syndrome
  Liver cancer
  Lobar holoprosencephaly
  Moyamoya disease
  Neoplasm
  Neoplasm of esophagus
  Panhypopituitarism
  Pituitary stalk interruption syndrome
  Precancerous condition
  Schizencephaly
  Solitary median maxillary central incisor syndrome
  Holoprosencephaly
  Adenocarcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Minimally invasive lung adenocarcinoma
  Bone osteosarcoma
  Childhood kidney Wilms tumor
  Hepatocellular carcinoma
  Hyperglycemia
  Osteosarcoma
  Wilms tumor
• UniProt ID: SIX3_HUMAN
• Pfam ID: PF00046 ; PF16878
• Sequence:
  MVFRSPLDLYSSHFLLPNFADSHHRSILLASSGGGNGAGGGGGAGGGSGGGNGAGGGGAG
  GAGGGGGGGSRAPPEELSMFQLPTLNFSPEQVASVCETLEETGDIERLGRFLWSLPVAPG
  ACEAINKHESILRARAVVAFHTGNFRDLYHILENHKFTKESHGKLQAMWLEAHYQEAEKL
  RGRPLGPVDKYRVRKKFPLPRTIWDGEQKTHCFKERTRSLLREWYLQDPYPNPSKKRELA
  QATGLTPTQVGNWFKNRRQRDRAAAAKNRLQHQAIGPSGMRSLAEPGCPTHGSAESPSTA
  ASPTTSVSSLTERADTGTSILSVTSSDSECDV
• Function: Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 and CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is TLE5 and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 functions also in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway. Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway.

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Chondrosarcoma	DIS4I7JB	Definitive	Biomarker	[2]
Holoprosencephaly 2	DIS1302V	Definitive	Autosomal dominant	[3]
Holoprosencephaly 5	DIS2AK05	Definitive	Autosomal dominant	[4]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[5]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[6]
Alobar holoprosencephaly	DISON1K9	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[8]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hypopituitarism	DIS1QT3G	Strong	Biomarker	[10]
Kallmann syndrome	DISO3HDG	Strong	Biomarker	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[12]
Lobar holoprosencephaly	DISVK1YW	Strong	Biomarker	[4]
Moyamoya disease	DISO62CA	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[8]
Panhypopituitarism	DISAKJ4T	Strong	Biomarker	[14]
Pituitary stalk interruption syndrome	DISGSN5T	Strong	Biomarker	[14]
Precancerous condition	DISV06FL	Strong	Biomarker	[12]
Schizencephaly	DISZVYEC	Strong	Genetic Variation	[15]
Solitary median maxillary central incisor syndrome	DISEWCUH	Strong	Genetic Variation	[16]
Holoprosencephaly	DISR35EC	Supportive	Autosomal recessive	[17]
Adenocarcinoma	DIS3IHTY	Disputed	Altered Expression	[18]
Lung adenocarcinoma	DISD51WR	Disputed	Altered Expression	[18]
Lung cancer	DISCM4YA	Disputed	Biomarker	[18]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[18]
Minimally invasive lung adenocarcinoma	DIS4W83X	Disputed	Altered Expression	[18]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[19]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[20]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[21]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[22]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[19]
Wilms tumor	DISB6T16	Limited	Biomarker	[20]

11 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 Homeobox protein SIX3 (SIX3).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein SIX3 (SIX3).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein SIX3 (SIX3).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Homeobox protein SIX3 (SIX3).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein SIX3 (SIX3).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Homeobox protein SIX3 (SIX3).	[26]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Homeobox protein SIX3 (SIX3).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox protein SIX3 (SIX3).	[26]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Homeobox protein SIX3 (SIX3).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein SIX3 (SIX3).	[31]
Manganese	DMKT129	Investigative	Manganese increases the expression of Homeobox protein SIX3 (SIX3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Homeobox protein SIX3 (SIX3).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein SIX3 (SIX3).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Homeobox protein SIX3 (SIX3).	[28]

References

• [1] The Homeotic Protein SIX3 Suppresses Carcinogenesis and Metastasis through Recruiting the LSD1/NuRD(MTA3) Complex.Theranostics. 2018 Jan 1;8(4):972-989. doi: 10.7150/thno.22328. eCollection 2018.
• [2] Coexpression of NOR1 and SIX3 proteins in extraskeletal myxoid chondrosarcomas without detectable NR4A3 fusion genes.Cancer Genet Cytogenet. 2004 Jul 15;152(2):101-7. doi: 10.1016/j.cancergencyto.2003.11.011.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999 Jun;22(2):196-8. doi: 10.1038/9718.
• [5] CellBIC: bimodality-based top-down clustering of single-cell RNA sequencing data reveals hierarchical structure of the cell type.Nucleic Acids Res. 2018 Nov 30;46(21):e124. doi: 10.1093/nar/gky698.
• [6] Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members.J Neurooncol. 2017 Jul;133(3):509-518. doi: 10.1007/s11060-017-2476-y. Epub 2017 Jun 22.
• [7] SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.J Hematol Oncol. 2017 Jun 8;10(1):115. doi: 10.1186/s13045-017-0483-2.
• [8] Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer.Anticancer Drugs. 2019 Jul;30(6):596-603. doi: 10.1097/CAD.0000000000000751.
• [9] RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions.J Virol. 2012 May;86(10):5660-73. doi: 10.1128/JVI.06338-11. Epub 2012 Mar 21.
• [10] Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development.Dev Biol. 2008 Dec 15;324(2):322-33. doi: 10.1016/j.ydbio.2008.08.008. Epub 2008 Aug 18.
• [11] Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.Mol Neurobiol. 2018 Nov;55(11):8709-8727. doi: 10.1007/s12035-018-1013-0. Epub 2018 Mar 27.
• [12] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [13] A novel heterozygous missense mutation 377T > C (V126A) of TGIF gene in a family segregated with holoprosencephaly and moyamoya disease.Prenat Diagn. 2006 Mar;26(3):226-30. doi: 10.1002/pd.1385.
• [14] Pituitary stalk interruption syndrome and isolated pituitary hypoplasia may be caused by mutations in holoprosencephaly-related genes.J Clin Endocrinol Metab. 2013 Apr;98(4):E779-84. doi: 10.1210/jc.2012-3982. Epub 2013 Mar 8.
• [15] Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly.Hum Genet. 2010 Mar;127(5):555-61. doi: 10.1007/s00439-010-0797-4. Epub 2010 Feb 16.
• [16] SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature.Am J Med Genet. 2001 Jul 22;102(1):1-10. doi: 10.1002/1096-8628(20010722)102:1<1::aid-ajmg1336>3.0.co;2-u.
• [17] Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018 Jun;178(2):258-269. doi: 10.1002/ajmg.c.31619. Epub 2018 May 22.
• [18] Down-regulation of SIX3 is associated with clinical outcome in lung adenocarcinoma.PLoS One. 2013 Aug 16;8(8):e71816. doi: 10.1371/journal.pone.0071816. eCollection 2013.
• [19] Integrated bioinformatics analysis of miRNA expression in osteosarcoma.Artif Cells Nanomed Biotechnol. 2017 Aug;45(5):936-943. doi: 10.1080/21691401.2016.1196456. Epub 2016 Jun 17.
• [20] Array CGH Analysis of Paired Blood and Tumor Samples from Patients with Sporadic Wilms Tumor.PLoS One. 2015 Aug 28;10(8):e0136812. doi: 10.1371/journal.pone.0136812. eCollection 2015.
• [21] A novel long noncoding RNA lncWDR26 suppresses the growth and metastasis of hepatocellular carcinoma cells through interaction with SIX3.Am J Cancer Res. 2018 Apr 1;8(4):688-698. eCollection 2018.
• [22] Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human Cell Function.Cell Metab. 2016 May 10;23(5):909-20. doi: 10.1016/j.cmet.2016.04.002. Epub 2016 Apr 28.
• [23] 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.
• [24] 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.
• [25] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [30] 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.
• [31] 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.
• [32] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.