Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25J0F7)

• DOT Name: Paired box protein Pax-9 (PAX9)
• Gene Name: PAX9
• Related Disease:
  Neoplasm
  Tooth agenesis, selective, 3
  Advanced cancer
  Brain-lung-thyroid syndrome
  Breast cancer
  Breast carcinoma
  Cleft lip
  Cytomegalovirus infection
  Ectodermal dysplasia
  Esophageal squamous cell carcinoma
  Familial prostate carcinoma
  Hereditary progressive chorea without dementia
  Isolated cleft lip
  Medullary thyroid gland carcinoma
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Spondylocostal dysostosis
  Cleft palate
  Isolated cleft palate
  Rhabdomyosarcoma
  Tooth agenesis
  Bone development disease
  Melanocytic nevus
  Tooth agenesis, selective, 1
• UniProt ID: PAX9_HUMAN
• Pfam ID: PF00292
• Sequence:
  MEPAFGEVNQLGGVFVNGRPLPNAIRLRIVELAQLGIRPCDISRQLRVSHGCVSKILARY
  NETGSILPGAIGGSKPRVTTPTVVKHIRTYKQRDPGIFAWEIRDRLLADGVCDKYNVPSV
  SSISRILRNKIGNLAQQGHYDSYKQHQPTPQPALPYNHIYSYPSPITAAAAKVPTPPGVP
  AIPGSVAMPRTWPSSHSVTDILGIRSITDQVSDSSPYHSPKVEEWSSLGRNNFPAAAPHA
  VNGLEKGALEQEAKYGQAPNGLPAVGSFVSASSMAPYPTPAQVSPYMTYSAAPSGYVAGH
  GWQHAGGTSLSPHNCDIPASLAFKGMQAAREGSHSVTASAL
• Function: Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs.

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Tooth agenesis, selective, 3	DISO2RLG	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Brain-lung-thyroid syndrome	DISSL12Z	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cleft lip	DISV3XW6	Strong	Genetic Variation	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Genetic Variation	[8]
Ectodermal dysplasia	DISLRS4M	Strong	Biomarker	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[10]
Hereditary progressive chorea without dementia	DISW33PR	Strong	Genetic Variation	[11]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[7]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Altered Expression	[12]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[10]
Spondylocostal dysostosis	DISTPWFK	Strong	Altered Expression	[13]
Cleft palate	DIS6G5TF	moderate	Biomarker	[14]
Isolated cleft palate	DISV80CD	moderate	Biomarker	[14]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[15]
Tooth agenesis	DIS1PWC7	Supportive	Autosomal dominant	[16]
Bone development disease	DISVKAZS	Limited	Genetic Variation	[17]
Melanocytic nevus	DISYS32D	Limited	Altered Expression	[18]
Tooth agenesis, selective, 1	DIS84ERL	Limited	Genetic Variation	[19]

1 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 Paired box protein Pax-9 (PAX9).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Paired box protein Pax-9 (PAX9).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Paired box protein Pax-9 (PAX9).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Paired box protein Pax-9 (PAX9).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Paired box protein Pax-9 (PAX9).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Paired box protein Pax-9 (PAX9).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Paired box protein Pax-9 (PAX9).	[23]

References

• [1] Bridging the molecular divide: alcohol-induced downregulation of PAX9 and tumour development.J Pathol. 2018 Apr;244(4):386-388. doi: 10.1002/path.5041. Epub 2018 Feb 26.
• [2] 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.
• [3] Prognostic value of PAX9 in patients with esophageal squamous cell carcinoma and its prediction value to radiation sensitivity.Mol Med Rep. 2017 Jul;16(1):806-816. doi: 10.3892/mmr.2017.6626. Epub 2017 May 25.
• [4] The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency. Eur J Med Genet. 2018 Jul;61(7):393-398. doi: 10.1016/j.ejmg.2018.02.007. Epub 2018 Feb 22.
• [5] Large-scale genotyping identifies 41 new loci associated with breast cancer risk.Nat Genet. 2013 Apr;45(4):353-61, 361e1-2. doi: 10.1038/ng.2563.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] SNPs and interaction analyses of IRF6, MSX1 and PAX9 genes in patients with nonsyndromic cleft lip with or without palate.Mol Med Rep. 2013 Oct;8(4):1228-34. doi: 10.3892/mmr.2013.1617. Epub 2013 Aug 6.
• [8] Interaction between HCMV infection and PAX9 gene polymorphisms in low birth weight infants.J Matern Fetal Neonatal Med. 2016;29(12):2040-3. doi: 10.3109/14767058.2015.1073253. Epub 2015 Aug 26.
• [9] GREMLIN 2 Mutations and Dental Anomalies.J Dent Res. 2015 Dec;94(12):1646-52. doi: 10.1177/0022034515608168. Epub 2015 Sep 28.
• [10] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [11] New syndromic form of benign hereditary chorea is associated with a deletion of TITF-1 and PAX-9 contiguous genes.Mov Disord. 2006 Dec;21(12):2237-40. doi: 10.1002/mds.21135.
• [12] Functional analysis of Nkx2.1 and Pax9 for calcitonin gene transcription.Gen Comp Endocrinol. 2007 Jun-Jul;152(2-3):259-66. doi: 10.1016/j.ygcen.2007.02.017. Epub 2007 Feb 28.
• [13] Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review.Am J Med Genet A. 2003 Jul 15;120A(2):241-6. doi: 10.1002/ajmg.a.20192.
• [14] The Function and Regulatory Network of Pax9 Gene in Palate Development.J Dent Res. 2019 Mar;98(3):277-287. doi: 10.1177/0022034518811861. Epub 2018 Dec 24.
• [15] TGF-1 suppression of microRNA-450b-5p expression: a novel mechanism for blocking myogenic differentiation of rhabdomyosarcoma.Oncogene. 2014 Apr 17;33(16):2075-86. doi: 10.1038/onc.2013.165. Epub 2013 May 13.
• [16] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [17] Defining the breakpoints of proximal chromosome 14q rearrangements in nine patients using flow-sorted chromosomes.Am J Med Genet. 2001 Aug 1;102(2):173-82. doi: 10.1002/ajmg.1418.
• [18] PAX4 has the potential to function as a tumor suppressor in human melanoma.Int J Oncol. 2008 Nov;33(5):1065-71.
• [19] Novel missense mutation in PAX9 gene associated with familial tooth agenesis.J Oral Pathol Med. 2013 Jan;42(1):99-105. doi: 10.1111/j.1600-0714.2012.01193.x. Epub 2012 Jul 2.
• [20] 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.
• [21] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [22] 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.
• [23] 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.
• [24] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.