Details of Drug Off-Target (DOT)

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

• DOT Name: Forkhead box protein L2 (FOXL2)
• Gene Name: FOXL2
• Related Disease:
  Blepharophimosis, ptosis, and epicanthus inversus syndrome
  46,XX testicular disorder of sex development
  Adenoma
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Chromosomal disorder
  Colorectal carcinoma
  Disease of orbital part of eye adnexa
  Disorder of sexual differentiation
  Duane retraction syndrome
  Endometrium adenocarcinoma
  Epithelial neoplasm
  Gastrointestinal stromal tumour
  Gonorrhea
  Isolated congenital microcephaly
  Keloid
  Liver cancer
  Lung squamous cell carcinoma
  Malignant soft tissue neoplasm
  Mobius syndrome
  Ovarian cancer
  Ovarian dysfunction
  Ovarian neoplasm
  Perrault syndrome
  Ptosis
  Sarcoma
  Trichohepatoenteric syndrome
  Small-cell lung cancer
  Colorectal neoplasm
  Adenocarcinoma
  Advanced cancer
  Atrial septal defect
  Familial male-limited precocious puberty
  Gastric cancer
  Intellectual disability
  Metastatic malignant neoplasm
  Premature ovarian failure 3
  Retinoblastoma
  Stomach cancer
• UniProt ID: FOXL2_HUMAN
• PDB ID: 7VOU; 7VOV
• Pfam ID: PF00250
• Sequence:
  MMASYPEPEDAAGALLAPETGRTVKEPEGPPPSPGKGGGGGGGTAPEKPDPAQKPPYSYV
  ALIAMAIRESAEKRLTLSGIYQYIIAKFPFYEKNKKGWQNSIRHNLSLNECFIKVPREGG
  GERKGNYWTLDPACEDMFEKGNYRRRRRMKRPFRPPPAHFQPGKGLFGAGGAAGGCGVAG
  AGADGYGYLAPPKYLQSGFLNNSWPLPQPPSPMPYASCQMAAAAAAAAAAAAAAGPGSPG
  AAAVVKGLAGPAASYGPYTRVQSMALPPGVVNSYNGLGGPPAAPPPPPHPHPHPHAHHLH
  AAAAPPPAPPHHGAAAPPPGQLSPASPATAAPPAPAPTSAPGLQFACARQPELAMMHCSY
  WDHDSKTGALHSRLDL
• Function: Transcriptional regulator. Critical factor essential for ovary differentiation and maintenance, and repression of the genetic program for somatic testis determination. Prevents trans-differentiation of ovary to testis through transcriptional repression of the Sertoli cell-promoting gene SOX9. Has apoptotic activity in ovarian cells. Suppresses ESR1-mediated transcription of PTGS2/COX2 stimulated by tamoxifen. Is a regulator of CYP19 expression. Participates in SMAD3-dependent transcription of FST via the intronic SMAD-binding element. Is a transcriptional repressor of STAR. Activates SIRT1 transcription under cellular stress conditions. Activates transcription of OSR2.
• Tissue Specificity: In addition to its expression in the developing eyelid, it is transcribed very early in somatic cells of the developing gonad (before sex determination) and its expression persists in the follicular cells of the adult ovary.
• Reactome Pathway: SUMOylation of transcription factors (R-HSA-3232118)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blepharophimosis, ptosis, and epicanthus inversus syndrome	DISN43YC	Definitive	Autosomal dominant	[1]
46,XX testicular disorder of sex development	DISTZBTV	Strong	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Disease of orbital part of eye adnexa	DISGWPWX	Strong	Biomarker	[7]
Disorder of sexual differentiation	DISRMAEZ	Strong	Altered Expression	[8]
Duane retraction syndrome	DISOEBK2	Strong	Genetic Variation	[9]
Endometrium adenocarcinoma	DISY6744	Strong	Genetic Variation	[10]
Epithelial neoplasm	DIS0T594	Strong	Genetic Variation	[11]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Altered Expression	[4]
Gonorrhea	DISQ5AO6	Strong	Genetic Variation	[12]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[13]
Keloid	DISV09JY	Strong	Biomarker	[14]
Liver cancer	DISDE4BI	Strong	Altered Expression	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[4]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[15]
Mobius syndrome	DIS9YXP5	Strong	Genetic Variation	[16]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[17]
Ovarian dysfunction	DIST09IB	Strong	Genetic Variation	[18]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[19]
Perrault syndrome	DISG2YOV	Strong	Biomarker	[20]
Ptosis	DISJZNIY	Strong	Genetic Variation	[21]
Sarcoma	DISZDG3U	Strong	Biomarker	[15]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[21]
Small-cell lung cancer	DISK3LZD	moderate	Genetic Variation	[22]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[23]
Adenocarcinoma	DIS3IHTY	Limited	Genetic Variation	[24]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[25]
Atrial septal defect	DISJT76B	Limited	Genetic Variation	[26]
Familial male-limited precocious puberty	DISNNKVB	Limited	Altered Expression	[27]
Gastric cancer	DISXGOUK	Limited	Biomarker	[28]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[29]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[28]
Premature ovarian failure 3	DISXO7WJ	Limited	Unknown	[30]
Retinoblastoma	DISVPNPB	Limited	Altered Expression	[31]
Stomach cancer	DISKIJSX	Limited	Biomarker	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Forkhead box protein L2 (FOXL2).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Forkhead box protein L2 (FOXL2).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Forkhead box protein L2 (FOXL2).	[39]

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 Forkhead box protein L2 (FOXL2).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Forkhead box protein L2 (FOXL2).	[34]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Forkhead box protein L2 (FOXL2).	[35]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Forkhead box protein L2 (FOXL2).	[36]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Forkhead box protein L2 (FOXL2).	[36]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Forkhead box protein L2 (FOXL2).	[37]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.Nat Genet. 2001 Feb;27(2):159-66. doi: 10.1038/84781.
• [3] Expression of FOXL2 in human normal pituitaries and pituitary adenomas.Mod Pathol. 2011 Jun;24(6):765-73. doi: 10.1038/modpathol.2010.169. Epub 2011 Apr 8.
• [4] Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.Sci Rep. 2017 Apr 4;7(1):641. doi: 10.1038/s41598-017-00219-3.
• [5] FOXL2 suppresses proliferation, invasion and promotes apoptosis of cervical cancer cells.Int J Clin Exp Pathol. 2014 Mar 15;7(4):1534-43. eCollection 2014.
• [6] FOXL2 mutation and large-scale genomic imbalances in adult granulosa cell tumors of the ovary.Cancer Genet. 2011 Nov;204(11):596-602. doi: 10.1016/j.cancergen.2011.10.002.
• [7] Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.Clin Genet. 2003 Feb;63(2):117-20. doi: 10.1034/j.1399-0004.2003.00011.x.
• [8] Non-coding variation in disorders of sex development.Clin Genet. 2017 Feb;91(2):163-172. doi: 10.1111/cge.12911.
• [9] Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation.Clin Genet. 2005 Dec;68(6):520-3. doi: 10.1111/j.1399-0004.2005.00527.x.
• [10] Disparate genomic characteristics of concurrent endometrial adenocarcinoma and ovarian granulosa cell tumor, revealed by targeted next-generation sequencing.Pathol Res Pract. 2018 Aug;214(8):1231-1233. doi: 10.1016/j.prp.2018.06.009. Epub 2018 Jun 19.
• [11] Adult granulosa cell tumour-like areas occurring in ovarian epithelial neoplasms: report of a case series with investigation of FOXL2 mutation status.Histopathology. 2014 Apr;64(5):626-32. doi: 10.1111/his.12314. Epub 2013 Dec 12.
• [12] FOXL2: a central transcription factor of the ovary.J Mol Endocrinol. 2013 Dec 19;52(1):R17-33. doi: 10.1530/JME-13-0159. Print 2014 Feb.
• [13] Acquired microcephaly in blepharophimosis-ptosis-epicanthus inversus syndrome because of an interstitial 3q22.3q23 deletion.Pediatr Neurol. 2014 Jun;50(6):636-9. doi: 10.1016/j.pediatrneurol.2014.01.055. Epub 2014 Feb 10.
• [14] A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population.Nat Genet. 2010 Sep;42(9):768-71. doi: 10.1038/ng.645. Epub 2010 Aug 15.
• [15] Mutational analysis of PIK3CA, JAK2, BRAF, FOXL2, IDH1, AKT1 and EZH2 oncogenes in sarcomas.APMIS. 2012 Aug;120(8):635-9. doi: 10.1111/j.1600-0463.2012.02878.x. Epub 2012 Mar 24.
• [16] SOX14 is a candidate gene for limb defects associated with BPES and Mbius syndrome.Hum Genet. 2000 Mar;106(3):269-76. doi: 10.1007/s004390051037.
• [17] Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors.Int J Biochem Cell Biol. 2016 Mar;72:51-54. doi: 10.1016/j.biocel.2016.01.003. Epub 2016 Jan 11.
• [18] Differential apoptotic and proliferative activities of wild-type FOXL2 and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES)-associated mutant FOXL2 proteins.J Reprod Dev. 2014 Mar 7;60(1):14-20. doi: 10.1262/jrd.2013-090. Epub 2013 Nov 15.
• [19] Mutational analysis of FOXL2 p.C134W and expression of bone morphogenetic protein 2 in Japanese patients with granulosa cell tumor of ovary.J Obstet Gynaecol Res. 2014 May;40(5):1197-204. doi: 10.1111/jog.12324. Epub 2014 Apr 2.
• [20] Perrault syndrome: report of four new cases, review and exclusion of candidate genes.Am J Med Genet A. 2008 Mar 1;146A(5):661-4. doi: 10.1002/ajmg.a.32180.
• [21] Clinical characterization and identification of five novel FOXL2 pathogenic variants in a cohort of 12 Mexican subjects with the syndrome of blepharophimosis-ptosis-epicanthus inversus.Gene. 2019 Jul 20;706:62-68. doi: 10.1016/j.gene.2019.04.073. Epub 2019 Apr 29.
• [22] Recently characterized molecular events in uncommon gynaecological neoplasms and their clinical importance.Histopathology. 2016 Dec;69(6):903-913. doi: 10.1111/his.13058. Epub 2016 Oct 3.
• [23] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [24] FOXL2 C402G mutation detection using MALDI-TOF-MS in DNA extracted from Israeli granulosa cell tumors.Gynecol Oncol. 2011 Sep;122(3):580-4. doi: 10.1016/j.ygyno.2011.05.008.
• [25] KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.Nat Commun. 2018 Jun 27;9(1):2496. doi: 10.1038/s41467-018-04950-x.
• [26] Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES).Med Sci Monit. 2018 Mar 5;24:1340-1358. doi: 10.12659/msm.908923.
• [27] Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children.Fertil Steril. 2007 Apr;87(4):896-901. doi: 10.1016/j.fertnstert.2006.11.016.
• [28] HMGA2-FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer.Clin Cancer Res. 2017 Jul 1;23(13):3461-3473. doi: 10.1158/1078-0432.CCR-16-2180. Epub 2017 Jan 24.
• [29] Further molecular and clinical delineation of the Wisconsin syndrome phenotype associated with interstitial 3q24q25 deletions.Am J Med Genet A. 2011 Jan;155A(1):106-12. doi: 10.1002/ajmg.a.33715. Epub 2010 Dec 15.
• [30] Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod. 2002 Aug;8(8):729-33. doi: 10.1093/molehr/8.8.729.
• [31] Aberrant granulosa cell-fate related to inactivated p53/Rb signaling contributes to granulosa cell tumors and to FOXL2 downregulation in the mouse ovary.Oncogene. 2020 Feb;39(9):1875-1890. doi: 10.1038/s41388-019-1109-7. Epub 2019 Nov 19.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [36] MiR-17-5p/FOXL2/CDKN1B signal programming in oocytes mediates transgenerational inheritance of diminished ovarian reserve in female offspring rats induced by prenatal dexamethasone exposure. Cell Biol Toxicol. 2023 Jun;39(3):867-883. doi: 10.1007/s10565-021-09645-6. Epub 2021 Sep 19.
• [37] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [38] 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.
• [39] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.