Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5IR5IT)

• DOT Name: Forkhead box protein E1 (FOXE1)
• Synonyms: Forkhead box protein E2; Forkhead-related protein FKHL15; HFKH4; HNF-3/fork head-like protein 5; HFKL5; Thyroid transcription factor 2; TTF-2
• Gene Name: FOXE1
• Related Disease:
  Bamforth-Lazarus syndrome
  Differentiated thyroid carcinoma
  Athyreosis
  CHARGE syndrome
  Cleft lip/palate
  Cleft palate
  Colitis
  Colorectal carcinoma
  Congenital hypothyroidism
  Graves disease
  Hepatocellular carcinoma
  Hypothyroidism
  Isolated cleft palate
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Orofacial cleft
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Breast cancer
  Breast carcinoma
  Cleft lip
  Cutaneous squamous cell carcinoma
  Female hypogonadism
  Isolated cleft lip
  Thyroid cancer
  Thyroid hypoplasia
  Thyroid tumor
  Thyroid gland carcinoma
  Hereditary hemochromatosis
  Multinodular goiter
  Nervous system disease
  Squamous cell carcinoma
• UniProt ID: FOXE1_HUMAN
• Pfam ID: PF00250
• Sequence:
  MTAESGPPPPQPEVLATVKEERGETAAGAGVPGEATGRGAGGRRRKRPLQRGKPPYSYIA
  LIAMAIAHAPERRLTLGGIYKFITERFPFYRDNPKKWQNSIRHNLTLNDCFLKIPREAGR
  PGKGNYWALDPNAEDMFESGSFLRRRKRFKRSDLSTYPAYMHDAAAAAAAAAAAAAAAAI
  FPGAVPAARPPYPGAVYAGYAPPSLAAPPPVYYPAASPGPCRVFGLVPERPLSPELGPAP
  SGPGGSCAFASAGAPATTTGYQPAGCTGARPANPSAYAAAYAGPDGAYPQGAGSAIFAAA
  GRLAGPASPPAGGSSGGVETTVDFYGRTSPGQFGALGACYNPGGQLGGASAGAYHARHAA
  AYPGGIDRFVSAM
• Function: Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription. Involved in proper palate formation, most probably through the expression of MSX1 and TGFB3 genes which are direct targets of this transcription factor. Also implicated in thyroid gland morphogenesis. May indirectly play a role in cell growth and migration through the regulation of WNT5A expression.
• Tissue Specificity: Detected in adult brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, heart, colon, small intestine testis and thymus. Expression was strongest in heart and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bamforth-Lazarus syndrome	DISDLIBD	Definitive	Autosomal recessive	[1]
Differentiated thyroid carcinoma	DIS1V20Y	Definitive	Genetic Variation	[2]
Athyreosis	DISBHHCU	Strong	Genetic Variation	[3]
CHARGE syndrome	DISKD3CW	Strong	Genetic Variation	[4]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[5]
Cleft palate	DIS6G5TF	Strong	Biomarker	[6]
Colitis	DISAF7DD	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[9]
Graves disease	DISU4KOQ	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[12]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[13]
Orofacial cleft	DIST1HG6	Strong	Genetic Variation	[15]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[16]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[17]
Breast cancer	DIS7DPX1	moderate	Biomarker	[18]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[18]
Cleft lip	DISV3XW6	moderate	Genetic Variation	[15]
Cutaneous squamous cell carcinoma	DIS3LXUG	moderate	Biomarker	[19]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[20]
Isolated cleft lip	DIS2O2JV	moderate	Genetic Variation	[15]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[21]
Thyroid hypoplasia	DISJG17B	moderate	Genetic Variation	[22]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[21]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Altered Expression	[21]
Hereditary hemochromatosis	DISVG5MT	Limited	Biomarker	[23]
Multinodular goiter	DISZQJH7	Limited	Biomarker	[24]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[25]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Forkhead box protein E1 (FOXE1).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Forkhead box protein E1 (FOXE1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Forkhead box protein E1 (FOXE1).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Forkhead box protein E1 (FOXE1).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Forkhead box protein E1 (FOXE1).	[31]

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 Forkhead box protein E1 (FOXE1).	[28]

References

• [1] 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.
• [2] Exploration of the association between FOXE1 gene polymorphism and differentiated thyroid cancer: a meta-analysis.BMC Med Genet. 2018 May 22;19(1):83. doi: 10.1186/s12881-018-0604-y.
• [3] Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis.Clin Chim Acta. 2017 Jul;470:36-41. doi: 10.1016/j.cca.2017.04.020. Epub 2017 Apr 25.
• [4] FOXE1 gene mutation screening by multiplex PCR/DHPLC in CHARGE syndrome and syndromic and non-syndromic cleft palate.J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 19;836(1-2):39-46. doi: 10.1016/j.jchromb.2006.03.028. Epub 2006 Apr 11.
• [5] Association between FOXE1 and non-syndromic orofacial clefts in a northeastern Chinese population.Br J Oral Maxillofac Surg. 2015 Oct;53(8):705-10. doi: 10.1016/j.bjoms.2015.05.021. Epub 2015 Jun 19.
• [6] A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing increased thyroidal gene expression.Thyroid. 2014 Apr;24(4):649-54. doi: 10.1089/thy.2013.0417. Epub 2014 Jan 23.
• [7] FOXE1 and SYNE1 genes hypermethylation panel as promising biomarker in colitis-associated colorectal neoplasia.Inflamm Bowel Dis. 2014 Feb;20(2):271-7. doi: 10.1097/01.MIB.0000435443.07237.ed.
• [8] Aberrant Methylation of FOXE1 Contributes to a Poor Prognosis for Patients with Colorectal Cancer.Ann Surg Oncol. 2016 Nov;23(12):3948-3955. doi: 10.1245/s10434-016-5289-x. Epub 2016 Jun 6.
• [9] Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism.Clin Chim Acta. 2017 May;468:76-80. doi: 10.1016/j.cca.2017.02.009. Epub 2017 Feb 16.
• [10] Genetic investigation of FOXE1 polyalanine tract in thyroid diseases: new insight on the role of FOXE1 in thyroid carcinoma.Cancer Biomark. 2010-2011;8(1):43-51. doi: 10.3233/DMA-2011-0824.
• [11] Double-negative feedback loop between microRNA-422a and forkhead box (FOX)G1/Q1/E1 regulates hepatocellular carcinoma tumor growth and metastasis.Hepatology. 2015 Feb;61(2):561-73. doi: 10.1002/hep.27491.
• [12] Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS).Pharmacogenet Genomics. 2017 Oct;27(10):356-362. doi: 10.1097/FPC.0000000000000299.
• [13] Profiling analysis of FOX gene family members identified FOXE1 as potential regulator of NSCLC development.Cell Mol Biol (Noisy-le-grand). 2016 Sep 30;62(11):57-62.
• [14] FOXE1 inhibits cell proliferation, migration and invasion of papillary thyroid cancer by regulating PDGFA.Mol Cell Endocrinol. 2019 Aug 1;493:110420. doi: 10.1016/j.mce.2019.03.010. Epub 2019 May 23.
• [15] FOXE1 polymorphisms and non-syndromic orofacial cleft susceptibility in a Chinese Han population.Oral Dis. 2016 May;22(4):274-9. doi: 10.1111/odi.12435. Epub 2016 Jan 20.
• [16] FOXE1 supports the tumor promotion of Gli2 on papillary thyroid carcinoma by the Wnt/-catenin pathway.J Cell Physiol. 2019 Aug;234(10):17739-17748. doi: 10.1002/jcp.28399. Epub 2019 Feb 22.
• [17] Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.Thyroid. 2017 Feb;27(2):236-252. doi: 10.1089/thy.2016.0285. Epub 2016 Dec 15.
• [18] Suppression of estrogen receptor-alpha transactivation by thyroid transcription factor-2 in breast cancer cells.Biochem Biophys Res Commun. 2012 May 11;421(3):532-7. doi: 10.1016/j.bbrc.2012.04.039. Epub 2012 Apr 13.
• [19] FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma.Br J Dermatol. 2010 May;162(5):1093-7. doi: 10.1111/j.1365-2133.2009.09560.x. Epub 2009 Oct 21.
• [20] FOXE1 polyalanine tract length screening by MLPA in idiopathic premature ovarian failure.Reprod Biol Endocrinol. 2011 Dec 16;9:158. doi: 10.1186/1477-7827-9-158.
• [21] FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1.Endocr Relat Cancer. 2020 Mar;27(3):137-151. doi: 10.1530/ERC-19-0156.
• [22] Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.BMC Endocr Disord. 2014 Aug 22;14:69. doi: 10.1186/1472-6823-14-69.
• [23] FOXE1, a new transcriptional target of GLI2 is expressed in human epidermis and basal cell carcinoma.J Invest Dermatol. 2004 May;122(5):1180-7. doi: 10.1111/j.0022-202X.2004.22505.x.
• [24] Somatic Mutations of FOXE1 in Papillary Thyroid Cancer.Thyroid. 2015 Aug;25(8):904-10. doi: 10.1089/thy.2015.0030. Epub 2015 Jun 19.
• [25] FKHL15, a new human member of the forkhead gene family located on chromosome 9q22.Genomics. 1997 May 1;41(3):390-6. doi: 10.1006/geno.1997.4692.
• [26] Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth. Mol Cancer Ther. 2013 Jul;12(7):1276-87. doi: 10.1158/1535-7163.MCT-12-0841. Epub 2013 Apr 17.
• [27] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [28] 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.
• [29] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.