Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFM1GKF)

• DOT Name: Transcription factor Ovo-like 2 (OVOL2)
• Synonyms: hOvo2; Zinc finger protein 339
• Gene Name: OVOL2
• Related Disease:
  Posterior polymorphous corneal dystrophy 1
  Bone osteosarcoma
  Breast neoplasm
  Carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Congenital hereditary endothelial dystrophy of cornea
  Corneal dystrophy
  Cutaneous squamous cell carcinoma
  Epithelial neoplasm
  Fuchs' endothelial dystrophy
  Lentivirus infection
  Lung adenocarcinoma
  Melanoma
  Microcephaly
  Mitochondrial DNA depletion syndrome 11
  Nasopharyngeal carcinoma
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Skin neoplasm
  Squamous cell carcinoma
  Corneal disease
  Hepatocellular carcinoma
  Niemann-Pick disease type C
  Congenital hereditary endothelial dystrophy type I
  Posterior polymorphous corneal dystrophy
  Advanced cancer
• UniProt ID: OVOL2_HUMAN
• Pfam ID: PF00096 ; PF13894 ; PF13912
• Sequence:
  MPKVFLVKRRSLGVSVRSWDELPDEKRADTYIPVGLGRLLHDPPEDCRSDGGSSSGSGSS
  SAGEPGGAESSSSPHAPESETPEPGDAEGPDGHLATKQRPVARSKIKFTTGTCSDSVVHS
  CDLCGKGFRLQRMLNRHLKCHNQVKRHLCTFCGKGFNDTFDLKRHVRTHTGIRPYKCNVC
  NKAFTQRCSLESHLKKIHGVQQQYAYKQRRDKLYVCEDCGYTGPTQEDLYLHVNSAHPGS
  SFLKKTSKKLAALLQGKLTSAHQENTSLSEEEERK
• Function: Zinc-finger transcription repressor factor. Plays a critical role in maintaining the identity of epithelial lineages by suppressing epithelial-to mesenchymal transition (EMT) mainly through the repression of ZEB1, an EMT inducer. Positively regulates neuronal differentiation. Suppresses cell cycling and terminal differentiation of keratinocytes by directly repressing MYC and NOTCH1. Important for the correct development of primordial germ cells in embryos. Plays dual functions in thermogenesis and adipogenesis to maintain energy balance. Essential for brown/beige adipose tissue-mediated thermogenesis, is necessary for the development of brown adipocytes. In white adipose tissues, limits adipogenesis by blocking CEBPA binding to its transcriptional targets and inhibiting its transcription factor activity.
• Tissue Specificity: Expressed in testis, ovary, heart and skeletal muscle . Expressed in the cornea, but absent from the corneal endothelium .

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Posterior polymorphous corneal dystrophy 1	DISVGA4Z	Definitive	Autosomal dominant	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[4]
Congenital hereditary endothelial dystrophy of cornea	DISHLPKQ	Strong	Genetic Variation	[5]
Corneal dystrophy	DISRDPA6	Strong	Biomarker	[6]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Altered Expression	[7]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[7]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Biomarker	[8]
Lentivirus infection	DISX17PY	Strong	Altered Expression	[9]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[9]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[11]
Mitochondrial DNA depletion syndrome 11	DISGJJ69	Strong	CausalMutation	[11]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[12]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[10]
Corneal disease	DISTUIM1	moderate	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[14]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[15]
Congenital hereditary endothelial dystrophy type I	DIS7XDS6	Supportive	Autosomal dominant	[1]
Posterior polymorphous corneal dystrophy	DISHAYH6	Supportive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]

2 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 Transcription factor Ovo-like 2 (OVOL2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor Ovo-like 2 (OVOL2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription factor Ovo-like 2 (OVOL2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcription factor Ovo-like 2 (OVOL2).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor Ovo-like 2 (OVOL2).	[19]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Transcription factor Ovo-like 2 (OVOL2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor Ovo-like 2 (OVOL2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor Ovo-like 2 (OVOL2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor Ovo-like 2 (OVOL2).	[24]

References

• [1] Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. Am J Hum Genet. 2016 Jan 7;98(1):75-89. doi: 10.1016/j.ajhg.2015.11.018. Epub 2015 Dec 31.
• [2] Ovol2 induces mesenchymal-epithelial transition via targeting ZEB1 in osteosarcoma.Onco Targets Ther. 2018 May 22;11:2963-2973. doi: 10.2147/OTT.S157119. eCollection 2018.
• [3] OVOL2 antagonizes TGF- signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis.Oncotarget. 2017 Jun 13;8(24):39401-39416. doi: 10.18632/oncotarget.17031.
• [4] OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors.Gastroenterology. 2016 Mar;150(3):659-671.e16. doi: 10.1053/j.gastro.2015.11.041. Epub 2015 Nov 24.
• [5] Fuchs Endothelial Corneal Dystrophy in a Heterozygous Carrier of Congenital Hereditary Endothelial Dystrophy Type 2 with a Novel Mutation in SLC4A11. Ophthalmic Genet. 2015;36(3):284-6. doi: 10.3109/13816810.2014.881510.
• [6] IC3D classification of corneal dystrophies--edition 2.Cornea. 2015 Feb;34(2):117-59. doi: 10.1097/ICO.0000000000000307.
• [7] Potential role of the OVOL1-OVOL2 axis and c-Myc in the progression of cutaneous squamous cell carcinoma.Mod Pathol. 2017 Jul;30(7):919-927. doi: 10.1038/modpathol.2016.169. Epub 2017 Mar 24.
• [8] Corneal dystrophy-causing SLC4A11 mutants: suitability for folding-correction therapy.Hum Mutat. 2014 Sep;35(9):1082-91. doi: 10.1002/humu.22601. Epub 2014 Jun 28.
• [9] Ovol2 gene inhibits the Epithelial-to-Mesenchymal Transition in lung adenocarcinoma by transcriptionally repressing Twist1.Gene. 2017 Feb 5;600:1-8. doi: 10.1016/j.gene.2016.11.034. Epub 2016 Nov 21.
• [10] The role of the OVOL1-OVOL2 axis in normal and diseased human skin.J Dermatol Sci. 2018 Jun;90(3):227-231. doi: 10.1016/j.jdermsci.2018.02.005. Epub 2018 Feb 12.
• [11] Homozygous c.359del variant in MGME1 is associated with early onset cerebellar ataxia.Eur J Med Genet. 2017 Oct;60(10):533-535. doi: 10.1016/j.ejmg.2017.07.010. Epub 2017 Jul 12.
• [12] OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma.Theranostics. 2018 Mar 8;8(8):2202-2216. doi: 10.7150/thno.24003. eCollection 2018.
• [13] Mutational spectrum of the SLC4A11 gene in autosomal recessive congenital hereditary endothelial dystrophy.Mol Vis. 2007 Jul 26;13:1327-32.
• [14] Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma.Biomed Pharmacother. 2019 Oct;118:109270. doi: 10.1016/j.biopha.2019.109270. Epub 2019 Aug 8.
• [15] OVOL2 in metastasis prevention in NPC.Theranostics. 2018 Mar 8;8(8):2242-2244. doi: 10.7150/thno.25181. eCollection 2018.
• [16] 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.
• [17] 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.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] 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.
• [20] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [24] 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.