Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein SIX2 (SIX2)
• Synonyms: Sine oculis homeobox homolog 2
• Gene Name: SIX2
• Related Disease:
  Advanced cancer
  Amyotrophic lateral sclerosis type 1
  Branchiootic syndrome 3
  Breast cancer
  Breast carcinoma
  Carcinoma
  Childhood kidney Wilms tumor
  Clear cell renal carcinoma
  Cleft palate
  Colorectal carcinoma
  Cystic kidney disease
  Familial amyotrophic lateral sclerosis
  Isolated cleft palate
  Kidney neoplasm
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Nephropathy
  Oculocerebrorenal syndrome
  Ptosis
  Renal cell carcinoma
  Renal dysplasia
  Vesicoureteral reflux
  Von hippel-lindau disease
  Hepatocellular carcinoma
  Triple negative breast cancer
  Glomerulosclerosis
  Non-small-cell lung cancer
  Congenital anomaly of kidney and urinary tract
  Frontonasal dysplasia
  Hyperglycemia
  Pneumonia
  Wilms tumor
• UniProt ID: SIX2_HUMAN
• Pfam ID: PF00046 ; PF16878
• Sequence:
  MSMLPTFGFTQEQVACVCEVLQQGGNIERLGRFLWSLPACEHLHKNESVLKAKAVVAFHR
  GNFRELYKILESHQFSPHNHAKLQQLWLKAHYIEAEKLRGRPLGAVGKYRVRRKFPLPRS
  IWDGEETSYCFKEKSRSVLREWYAHNPYPSPREKRELAEATGLTTTQVSNWFKNRRQRDR
  AAEAKERENNENSNSNSHNPLNGSGKSVLGSSEDEKTPSGTPDHSSSSPALLLSPPPPGL
  PSLHSLGHPPGPSAVPVPVPGGGGADPLQHHHGLQDSILNPMSANLVDLGS
• Function: Transcription factor that plays an important role in the development of several organs, including kidney, skull and stomach. During kidney development, maintains cap mesenchyme multipotent nephron progenitor cells in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud and cooperates with WNT9B to promote renewing progenitor cells proliferation. Acts through its interaction with TCF7L2 and OSR1 in a canonical Wnt signaling independent manner preventing transcription of differentiation genes in cap mesenchyme such as WNT4. Also acts independently of OSR1 to activate expression of many cap mesenchyme genes, including itself, GDNF and OSR1. During craniofacial development plays a role in growth and elongation of the cranial base through regulation of chondrocyte differentiation. During stomach organogenesis, controls pyloric sphincter formation and mucosal growth through regulation of a gene network including NKX2-5, BMPR1B, BMP4, SOX9 and GREM1. During branchial arch development, acts to mediate HOXA2 control over the insulin-like growth factor pathway. May also be involved in limb tendon and ligament development. Plays a role in cell proliferation and migration.
• Tissue Specificity: Strongly expressed in skeletal muscle. Expressed in Wilms' tumor and in the cap mesenchyme of fetal kidney (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[2]
Branchiootic syndrome 3	DIS62V4P	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Cystic kidney disease	DISRT1LM	Strong	Genetic Variation	[9]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[2]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[7]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Altered Expression	[11]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Nephropathy	DISXWP4P	Strong	Biomarker	[12]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[13]
Ptosis	DISJZNIY	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Renal dysplasia	DIS3DFGD	Strong	Altered Expression	[4]
Vesicoureteral reflux	DISUL6SA	Strong	Altered Expression	[9]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[15]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[16]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[1]
Glomerulosclerosis	DISJF20Z	Disputed	Genetic Variation	[17]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Biomarker	[11]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Biomarker	[18]
Frontonasal dysplasia	DISXV4YX	Limited	Genetic Variation	[3]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[19]
Pneumonia	DIS8EF3M	Limited	Genetic Variation	[20]
Wilms tumor	DISB6T16	Limited	Biomarker	[21]

6 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 SIX2 (SIX2).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeobox protein SIX2 (SIX2).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeobox protein SIX2 (SIX2).	[24]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Homeobox protein SIX2 (SIX2).	[25]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Homeobox protein SIX2 (SIX2).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Homeobox protein SIX2 (SIX2).	[28]

1 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 increases the methylation of Homeobox protein SIX2 (SIX2).	[27]

References

• [1] SIX2 Mediates Late-Stage Metastasis via Direct Regulation of SOX2 and Induction of a Cancer Stem Cell Program.Cancer Res. 2019 Feb 15;79(4):720-734. doi: 10.1158/0008-5472.CAN-18-1791. Epub 2019 Jan 3.
• [2] Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
• [3] Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development.J Dent Res. 2019 May;98(5):572-579. doi: 10.1177/0022034519835204. Epub 2019 Mar 24.
• [4] The pluripotent renal stem cell regulator SIX2 is activated in renal neoplasms and influences cellular proliferation and migration.Hum Pathol. 2013 Mar;44(3):336-45. doi: 10.1016/j.humpath.2012.05.021. Epub 2012 Sep 17.
• [5] Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms' tumor.Tumour Biol. 2015 Sep;36(10):7591-8. doi: 10.1007/s13277-015-3456-5. Epub 2015 Apr 29.
• [6] Transcription factor Six2 induces a stem cell-like phenotype in renal cell carcinoma cells.FEBS Open Bio. 2019 Oct;9(10):1808-1816. doi: 10.1002/2211-5463.12721. Epub 2019 Sep 19.
• [7] Six2 regulates Pax9 expression, palatogenesis and craniofacial bone formation.Dev Biol. 2020 Feb 15;458(2):246-256. doi: 10.1016/j.ydbio.2019.11.010. Epub 2019 Nov 23.
• [8] The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer.Theranostics. 2017 Feb 27;7(5):1114-1132. doi: 10.7150/thno.18175. eCollection 2017.
• [9] Should SIX2 be routinely tested in patients with isolated congenital abnormalities of kidneys and/or urinary tract (CAKUT)?.Eur J Med Genet. 2012 Dec;55(12):688-9. doi: 10.1016/j.ejmg.2012.06.003. Epub 2012 Jul 15.
• [10] The expression profile and clinic significance of the SIX family in non-small cell lung cancer.J Hematol Oncol. 2016 Nov 8;9(1):119. doi: 10.1186/s13045-016-0339-1.
• [11] Six2 promotes non-small cell lung cancer cell stemness via transcriptionally and epigenetically regulating E-cadherin.Cell Prolif. 2019 Jul;52(4):e12617. doi: 10.1111/cpr.12617. Epub 2019 Apr 22.
• [12] Misexpression of Six2 is associated with heritable frontonasal dysplasia and renal hypoplasia in 3H1 Br mice.Dev Dyn. 2008 Jul;237(7):1767-79. doi: 10.1002/dvdy.21587.
• [13] Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex.PLoS One. 2018 Feb 14;13(2):e0192635. doi: 10.1371/journal.pone.0192635. eCollection 2018.
• [14] SIX2 haploinsufficiency causes conductive hearing loss with ptosis in humans.J Hum Genet. 2016 Nov;61(11):917-922. doi: 10.1038/jhg.2016.86. Epub 2016 Jul 7.
• [15] Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis.Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16538-43. doi: 10.1073/pnas.1414789111. Epub 2014 Oct 30.
• [16] Six2 is negatively correlated with prognosis and facilitates epithelial-mesenchymal transition via TGF-/Smad signal pathway in hepatocellular carcinoma.Hepatobiliary Pancreat Dis Int. 2019 Dec;18(6):525-531. doi: 10.1016/j.hbpd.2019.09.005. Epub 2019 Sep 14.
• [17] Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.Int J Cancer. 2019 Mar 15;144(6):1391-1400. doi: 10.1002/ijc.31952. Epub 2018 Dec 3.
• [18] Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract.Kidney Int. 2014 Jun;85(6):1429-33. doi: 10.1038/ki.2013.508. Epub 2014 Jan 15.
• [19] 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.
• [20] Comparison of clinical features and outcomes of medically attended influenza A and influenza B in a defined population over four seasons: 2004-2005 through 2007-2008.Influenza Other Respir Viruses. 2012 Jan;6(1):37-43. doi: 10.1111/j.1750-2659.2011.00263.x. Epub 2011 May 25.
• [21] 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.
• [22] 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.
• [23] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [25] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [26] CRISPR-based DNA methylation editing of NNT rescues the cisplatin resistance of lung cancer cells by reducing autophagy. Arch Toxicol. 2023 Feb;97(2):441-456. doi: 10.1007/s00204-022-03404-0. Epub 2022 Nov 6.
• [27] 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.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.