Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7U62SW)

• DOT Name: OTU domain-containing protein 4 (OTUD4)
• Synonyms: EC 3.4.19.12; HIV-1-induced protein HIN-1
• Gene Name: OTUD4
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast fibrocystic disease
  Breast neoplasm
  Carcinoma of esophagus
  Cerebellar ataxia-hypogonadism syndrome
  Esophageal cancer
  Hypogonadism
  Influenza
  Neoplasm
  Neoplasm of esophagus
  Precancerous condition
  Pyropoikilocytosis, hereditary
  Small-cell lung cancer
  Squamous cell carcinoma
  Ductal breast carcinoma in situ
  Glioblastoma multiforme
  Nasopharyngeal carcinoma
  Neuroblastoma
  Niemann-Pick disease type C
  Non-small-cell lung cancer
  Lymphoma
  Malignant mesothelioma
  Retinoblastoma
• UniProt ID: OTUD4_HUMAN
• EC Number: 3.4.19.12
• Pfam ID: PF02338
• Sequence:
  MEAAVGVPDGGDQGGAGPREDATPMDAYLRKLGLYRKLVAKDGSCLFRAVAEQVLHSQSR
  HVEVRMACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIY
  REPNVSPSQVTENNFPEKVLLCFSNGNHYDIVYPIKYKESSAMCQSLLYELLYEKVFKTD
  VSKIVMELDTLEVADEDNSEISDSEDDSCKSKTAAAAADVNGFKPLSGNEQLKNNGNSTS
  LPLSRKVLKSLNPAVYRNVEYEIWLKSKQAQQKRDYSIAAGLQYEVGDKCQVRLDHNGKF
  LNADVQGIHSENGPVLVEELGKKHTSKNLKAPPPESWNTVSGKKMKKPSTSGQNFHSDVD
  YRGPKNPSKPIKAPSALPPRLQHPSGVRQHAFSSHSSGSQSQKFSSEHKNLSRTPSQIIR
  KPDRERVEDFDHTSRESNYFGLSPEERREKQAIEESRLLYEIQNRDEQAFPALSSSSVNQ
  SASQSSNPCVQRKSSHVGDRKGSRRRMDTEERKDKDSIHGHSQLDKRPEPSTLENITDDK
  YATVSSPSKSKKLECPSPAEQKPAEHVSLSNPAPLLVSPEVHLTPAVPSLPATVPAWPSE
  PTTFGPTGVPAPIPVLSVTQTLTTGPDSAVSQAHLTPSPVPVSIQAVNQPLMPLPQTLSL
  YQDPLYPGFPCNEKGDRAIVPPYSLCQTGEDLPKDKNILRFFFNLGVKAYSCPMWAPHSY
  LYPLHQAYLAACRMYPKVPVPVYPHNPWFQEAPAAQNESDCTCTDAHFPMQTEASVNGQM
  PQPEIGPPTFSSPLVIPPSQVSESHGQLSYQADLESETPGQLLHADYEESLSGKNMFPQP
  SFGPNPFLGPVPIAPPFFPHVWYGYPFQGFIENPVMRQNIVLPSDEKGELDLSLENLDLS
  KDCGSVSTVDEFPEARGEHVHSLPEASVSSKPDEGRTEQSSQTRKADTALASIPPVAEGK
  AHPPTQILNRERETVPVELEPKRTIQSLKEKTEKVKDPKTAADVVSPGANSVDSRVQRPK
  EESSEDENEVSNILRSGRSKQFYNQTYGSRKYKSDWGYSGRGGYQHVRSEESWKGQPSRS
  RDEGYQYHRNVRGRPFRGDRRRSGMGDGHRGQHT
• Function: Deubiquitinase which hydrolyzes the isopeptide bond between the ubiquitin C-terminus and the lysine epsilon-amino group of the target protein. May negatively regulate inflammatory and pathogen recognition signaling in innate immune response. Upon phosphorylation at Ser-202 and Ser-204 residues, via IL-1 receptor and Toll-like receptor signaling pathway, specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter protein triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators. Independently of the catalytic activity, acts as a scaffold for alternative deubiquitinases to assemble specific deubiquitinase-substrate complexes. Associates with USP7 and USP9X deubiquitinases to stabilize alkylation repair enzyme ALKBH3, thereby promoting the repair of alkylated DNA lesions.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Posttranslational Modification	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast fibrocystic disease	DISUM7ID	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[1]
Cerebellar ataxia-hypogonadism syndrome	DISUEBFP	Strong	Genetic Variation	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[1]
Hypogonadism	DISICMNI	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[2]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[1]
Precancerous condition	DISV06FL	Strong	Altered Expression	[8]
Pyropoikilocytosis, hereditary	DISZGN3B	Strong	Biomarker	[8]
Small-cell lung cancer	DISK3LZD	Strong	Posttranslational Modification	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[10]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[11]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[12]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Posttranslational Modification	[13]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[14]
Niemann-Pick disease type C	DIS492ZO	moderate	Posttranslational Modification	[13]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[15]
Lymphoma	DISN6V4S	Limited	Posttranslational Modification	[16]
Malignant mesothelioma	DISTHJGH	Limited	Posttranslational Modification	[16]
Retinoblastoma	DISVPNPB	Limited	Posttranslational Modification	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of OTU domain-containing protein 4 (OTUD4).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of OTU domain-containing protein 4 (OTUD4).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of OTU domain-containing protein 4 (OTUD4).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of OTU domain-containing protein 4 (OTUD4).	[20]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of OTU domain-containing protein 4 (OTUD4).	[21]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of OTU domain-containing protein 4 (OTUD4).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of OTU domain-containing protein 4 (OTUD4).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of OTU domain-containing protein 4 (OTUD4).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of OTU domain-containing protein 4 (OTUD4).	[22]

References

• [1] Promoter methylation of HIN-1 in the progression to esophageal squamous cancer.Epigenetics. 2008 Nov;3(6):336-41. doi: 10.4161/epi.3.6.7158. Epub 2008 Nov 8.
• [2] Applicability of HIN-1, MGMT and RASSF1A promoter methylation as biomarkers for detecting field cancerization in breast cancer.Breast Cancer Res. 2015 Sep 14;17(1):125. doi: 10.1186/s13058-015-0637-5.
• [3] Modulation of gene methylation by genistein or lycopene in breast cancer cells.Environ Mol Mutagen. 2008 Jan;49(1):36-45. doi: 10.1002/em.20363.
• [4] Lack of HIN-1 methylation defines specific breast tumor subtypes including medullary carcinoma of the breast and BRCA1-linked tumors.Cancer Biol Ther. 2003 Sep-Oct;2(5):559-63. doi: 10.4161/cbt.2.5.511.
• [5] Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet. 2014 Feb 15;23(4):1013-24. doi: 10.1093/hmg/ddt497. Epub 2013 Oct 9.
• [6] STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.Orphanet J Rare Dis. 2014 Sep 26;9:146. doi: 10.1186/s13023-014-0146-0.
• [7] Use of dried clinical samples for storing and detecting influenza RNA.Influenza Other Respir Viruses. 2011 Nov;5(6):413-7. doi: 10.1111/j.1750-2659.2011.00253.x. Epub 2011 Apr 18.
• [8] Sessile serrated adenomas and classical adenomas: an epigenetic perspective on premalignant neoplastic lesions of the gastrointestinal tract.Int J Cancer. 2011 Oct 15;129(8):1889-98. doi: 10.1002/ijc.25847. Epub 2011 Mar 11.
• [9] Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types.Mol Cancer Res. 2004 Sep;2(9):489-94.
• [10] Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens.Gynecol Oncol. 2010 Jan;116(1):99-104. doi: 10.1016/j.ygyno.2009.09.032.
• [11] Quantitative promoter hypermethylation profiles of ductal carcinoma in situ in North American and Korean women: Potential applications for diagnosis.Cancer Biol Ther. 2008 Sep;7(9):1398-406. doi: 10.4161/cbt.7.9.6425. Epub 2008 Sep 4.
• [12] HIN-1: a New Epigenetic Biomarker Crucial for Therapy Selection in Glioblastoma Multiforme.Mol Neurobiol. 2016 Apr;53(3):1802-1807. doi: 10.1007/s12035-015-9127-0. Epub 2015 Mar 11.
• [13] Promoter hypermethylation of high-in-normal 1 gene in primary nasopharyngeal carcinoma.Clin Cancer Res. 2003 Aug 1;9(8):3042-6.
• [14] Methylation of CASP8, DCR2, and HIN-1 in neuroblastoma is associated with poor outcome.Clin Cancer Res. 2007 Jun 1;13(11):3191-7. doi: 10.1158/1078-0432.CCR-06-2846.
• [15] OTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair.Cancer Cell Int. 2019 Apr 15;19:99. doi: 10.1186/s12935-019-0816-z. eCollection 2019.
• [16] Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies.Int J Cancer. 2005 Feb 10;113(4):600-4. doi: 10.1002/ijc.20622.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] 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.
• [21] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [22] 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.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [25] 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.