Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9PB547)

• DOT Name: Death-inducer obliterator 1 (DIDO1)
• Synonyms: DIO-1; hDido1; Death-associated transcription factor 1; DATF-1
• Gene Name: DIDO1
• Related Disease:
  Colorectal adenoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Advanced cancer
  Myelodysplastic syndrome
  Myelodysplastic/myeloproliferative neoplasm
  Myocardial infarction
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Melanoma
  Chronic renal failure
• UniProt ID: DIDO1_HUMAN
• PDB ID: 2M3H; 4L7X
• Pfam ID: PF00628 ; PF07744 ; PF07500
• Sequence:
  MDDKGDPSNEEAPKAIKPTSKEFRKTWGFRRTTIAKREGAGDAEADPLEPPPPQQQLGLS
  LRRSGRQPKRTERVEQFLTIARRRGRRSMPVSLEDSGEPTSCPATDAETASEGSVESASE
  TRSGPQSASTAVKERPASSEKVKGGDDHDDTSDSDSDGLTLKELQNRLRRKREQEPTERP
  LKGIQSRLRKKRREEGPAETVGSEASDTVEGVLPSKQEPENDQGVVSQAGKDDRESKLEG
  KAAQDIKDEEPGDLGRPKPECEGYDPNALYCICRQPHNNRFMICCDRCEEWFHGDCVGIS
  EARGRLLERNGEDYICPNCTILQVQDETHSETADQQEAKWRPGDADGTDCTSIGTIEQKS
  SEDQGIKGRIEKAANPSGKKKLKIFQPVIEAPGASKCIGPGCCHVAQPDSVYCSNDCILK
  HAAATMKFLSSGKEQKPKPKEKMKMKPEKPSLPKCGAQAGIKISSVHKRPAPEKKETTVK
  KAVVVPARSEALGKEAACESSTPSWASDHNYNAVKPEKTAAPSPSLLYKSTKEDRRSEEK
  AAAMAASKKTAPPGSAVGKQPAPRNLVPKKSSFANVAAATPAIKKPPSGFKGTIPKRPWL
  SATPSSGASAARQAGPAPAAATAASKKFPGSAALVGAVRKPVVPSVPMASPAPGRLGAMS
  AAPSQPNSQIRQNIRRSLKEILWKRVNDSDDLIMTENEVGKIALHIEKEMFNLFQVTDNR
  YKSKYRSIMFNLKDPKNQGLFHRVLREEISLAKLVRLKPEELVSKELSTWKERPARSVME
  SRTKLHNESKKTAPRQEAIPDLEDSPPVSDSEEQQESARAVPEKSTAPLLDVFSSMLKDT
  TSQHRAHLFDLNCKICTGQVPSAEDEPAPKKQKLSASVKKEDLKSKHDSSAPDPAPDSAD
  EVMPEAVPEVASEPGLESASHPNVDRTYFPGPPGDGHPEPSPLEDLSPCPASCGSGVVTT
  VTVSGRDPRTAPSSSCTAVASAASRPDSTHMVEARQDVPKPVLTSVMVPKSILAKPSSSP
  DPRYLSVPPSPNISTSESRSPPEGDTTLFLSRLSTIWKGFINMQSVAKFVTKAYPVSGCF
  DYLSEDLPDTIHIGGRIAPKTVWDYVGKLKSSVSKELCLIRFHPATEEEEVAYISLYSYF
  SSRGRFGVVANNNRHVKDLYLIPLSAQDPVPSKLLPFEGPGLESPRPNIILGLVICQKIK
  RPANSGELDKMDEKRTRLQPEEADVPAYPKVATVPQSEKKPSKYPLCSADAAVSTTPPGS
  PPPPPPLPEPPVLKVLSSLKPAAPSPATAATTAAAASTAASSTASSASKTASPLEHILQT
  LFGKKKSFDPSAREPPGSTAGLPQEPKTTAEDGVPAPPLLDPIVQQFGQFSKDKALEEEE
  DDRPYDPEEEYDPERAFDTQLVERGRRHEVERAPEAAAAEREEVAYDPEDETILEEAKVT
  VDDLPNRMCADVRRNSVERPAEPVAGAATPSLVEQQKMLEELNKQIEEQKRQLEEQEEAL
  RQQRAAVGVSMAHFSVSDALMSPPPKSSLPKAELFQQEQQSADKPASLPPASQASNHRDP
  RQARRLATETGEGEGEPLSRLSARGAQGALPERDASRGGLVGQAPMPVPEEKEPASSPWA
  SGEKPPAGSEQDGWKAEPGEGTRPATVGDSSARPARRVLLPTPPCGALQPGFPLQHDGER
  DPFTCPGFASQDKALGSAQYEDPRNLHSAGRSSSPAGETEGDREPQARPGEGTAPLPPPG
  QKVGGSQPPFQGQREPGPHALGMSGLHGPNFPGPRGPAPPFPEENIASNDGPRGPPPARF
  GAQKGPIPSLFSGQHGPPPYGDSRGPSPSYLGGPRGVAPSQFEERKDPHGEKREFQDAPY
  NEVTGAPAQFEGTEQAPFLGSRGGAPFQFGGQRRPLLSQLKGPRGGPPPSQFGGQRGPPP
  GHFVGPRGPHPSQFETARGPHPNQFEGPRGQAPNFMPGPRGIQPQQFEDQRVHSPPRFTN
  QRAPAPLQFGGLRGSAPFSEKNEQTPSRFHFQGQAPQVMKPGPRPLLELPSHPPQHRKDR
  WEEAGPPSALSSSAPGQGPEADGQWASADFREGKGHEYRNQTFEGRQRERFDVGPKEKPL
  EEPDAQGRASEDRRRERERGRNWSRERDWDRPREWDRHRDKDSSRDWDRNRERSANRDRE
  READRGKEWDRSRERSRNRERERDRRRDRDRSRSRERDRDKARDRERGRDRKDRSKSKES
  ARDPKPEASRASDAGTASQA
• Function: Putative transcription factor, weakly pro-apoptotic when overexpressed. Tumor suppressor. Required for early embryonic stem cell development; [Isoform 2]: Displaces isoform 4 at the onset of differentiation, required for repression of stemness genes.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal adenoma	DISTSVHM	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	moderate	Altered Expression	[7]
Chronic renal failure	DISGG7K6	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Death-inducer obliterator 1 (DIDO1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Death-inducer obliterator 1 (DIDO1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Death-inducer obliterator 1 (DIDO1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Death-inducer obliterator 1 (DIDO1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Death-inducer obliterator 1 (DIDO1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Death-inducer obliterator 1 (DIDO1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Death-inducer obliterator 1 (DIDO1).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Death-inducer obliterator 1 (DIDO1).	[17]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Death-inducer obliterator 1 (DIDO1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Death-inducer obliterator 1 (DIDO1).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Death-inducer obliterator 1 (DIDO1).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Death-inducer obliterator 1 (DIDO1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Death-inducer obliterator 1 (DIDO1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Death-inducer obliterator 1 (DIDO1).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Death-inducer obliterator 1 (DIDO1).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Death-inducer obliterator 1 (DIDO1).	[27]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Death-inducer obliterator 1 (DIDO1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Death-inducer obliterator 1 (DIDO1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Death-inducer obliterator 1 (DIDO1).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Death-inducer obliterator 1 (DIDO1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Death-inducer obliterator 1 (DIDO1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Death-inducer obliterator 1 (DIDO1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Death-inducer obliterator 1 (DIDO1).	[25]

References

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• [2] Correlation between SALL4 stemness marker and bone morphogenetic protein signaling genes in esophageal squamous cell carcinoma.J Biochem Mol Toxicol. 2019 Mar;33(3):e22262. doi: 10.1002/jbt.22262. Epub 2018 Nov 15.
• [3] Exome sequencing in 51 early onset non-familial CRC cases.Mol Genet Genomic Med. 2019 May;7(5):e605. doi: 10.1002/mgg3.605. Epub 2019 Feb 27.
• [4] Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms.J Clin Invest. 2005 Sep;115(9):2351-62. doi: 10.1172/JCI24177. Epub 2005 Aug 25.
• [5] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [6] Identification of TWIST-interacting genes in prostate cancer.Sci China Life Sci. 2017 Apr;60(4):386-396. doi: 10.1007/s11427-016-0262-6. Epub 2017 Jan 22.
• [7] Death inducer-obliterator 1 (Dido1) is a BMP target gene and promotes BMP-induced melanoma progression.Oncogene. 2013 Feb 14;32(7):837-48. doi: 10.1038/onc.2012.115. Epub 2012 Apr 2.
• [8] The relationship between inflammatory factors, oxidative stress and DIO-1 concentration in patients with chronic renal failure accompanied with or without euthyroid sick syndrome.J Int Med Res. 2018 Oct;46(10):4061-4070. doi: 10.1177/0300060518778190. Epub 2018 Aug 28.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
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• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [18] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [27] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [28] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.