Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS6JFR0)

• DOT Name: E3 ubiquitin-protein ligase TRIM8 (TRIM8)
• Synonyms: EC 2.3.2.27; Glioblastoma-expressed RING finger protein; RING finger protein 27; RING-type E3 ubiquitin transferase TRIM8; Tripartite motif-containing protein 8
• Gene Name: TRIM8
• Related Disease:
  Advanced cancer
  Focal segmental glomerulosclerosis and neurodevelopmental syndrome
  Neoplasm
  Adult glioblastoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Eosinophilic esophagitis
  Epileptic encephalopathy
  Ethylmalonic encephalopathy
  Fatty liver disease
  Glioblastoma multiforme
  Glioma
  Intellectual disability
  Keratitis
  Metabolic disorder
  Nephrotic syndrome
  Prostate cancer
  Prostate carcinoma
  Psoriatic arthritis
  Infantile spasm
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
• UniProt ID: TRIM8_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13445
• Sequence:
  MAENWKNCFEEELICPICLHVFVEPVQLPCKHNFCRGCIGEAWAKDSGLVRCPECNQAYN
  QKPGLEKNLKLTNIVEKFNALHVEKPPAALHCVFCRRGPPLPAQKVCLRCEAPCCQSHVQ
  THLQQPSTARGHLLVEADDVRAWSCPQHNAYRLYHCEAEQVAVCQYCCYYSGAHQGHSVC
  DVEIRRNEIRKMLMKQQDRLEEREQDIEDQLYKLESDKRLVEEKVNQLKEEVRLQYEKLH
  QLLDEDLRQTVEVLDKAQAKFCSENAAQALHLGERMQEAKKLLGSLQLLFDKTEDVSFMK
  NTKSVKILMDRTQTCTSSSLSPTKIGHLNSKLFLNEVAKKEKQLRKMLEGPFSTPVPFLQ
  SVPLYPCGVSSSGAEKRKHSTAFPEASFLETSSGPVGGQYGAAGTASGEGQSGQPLGPCS
  STQHLVALPGGAQPVHSSPVFPPSQYPNGSAAQQPMLPQYGGRKILVCSVDNCYCSSVAN
  HGGHQPYPRSGHFPWTVPSQEYSHPLPPTPSVPQSLPSLAVRDWLDASQQPGHQDFYRVY
  GQPSTKHYVTS
• Function: E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response. Participates in the activation of interferon-gamma signaling by promoting proteasomal degradation of the repressor SOCS1. Plays a positive role in the TNFalpha and IL-1beta signaling pathways. Mechanistically, induces the 'Lys-63'-linked polyubiquitination of MAP3K7/TAK1 component leading to the activation of NF-kappa-B. Modulates also STAT3 activity through negative regulation of PIAS3, either by degradation of PIAS3 through the ubiquitin-proteasome pathway or exclusion of PIAS3 from the nucleus. Negatively regulates TLR3/4-mediated innate immune response by catalyzing 'Lys-6'- and 'Lys-33'-linked polyubiquitination of TICAM1 and thereby disrupting the TICAM1-TBK1 interaction.
• Tissue Specificity: Widely expressed. Expressed in glomerular podocytes of kidneys.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Focal segmental glomerulosclerosis and neurodevelopmental syndrome	DIS0ILI1	Definitive	Autosomal dominant	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Eosinophilic esophagitis	DISR8WSB	Strong	Biomarker	[5]
Epileptic encephalopathy	DISZOCA3	Strong	GermlineCausalMutation	[6]
Ethylmalonic encephalopathy	DISH7SB9	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Keratitis	DISMFOEI	Strong	Biomarker	[9]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[7]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[10]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[11]
Psoriatic arthritis	DISLWTG2	Strong	Biomarker	[9]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[6]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Biomarker	[12]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Disputed	Biomarker	[12]

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 E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[26]

14 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 E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[21]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[22]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase TRIM8 (TRIM8).	[28]

References

• [1] TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role.Genes (Basel). 2017 Nov 28;8(12):354. doi: 10.3390/genes8120354.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways.Biochim Biophys Acta Gen Subj. 2019 Feb;1863(2):491-501. doi: 10.1016/j.bbagen.2018.12.001. Epub 2018 Dec 5.
• [4] TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours.Mol Cancer. 2017 Mar 21;16(1):67. doi: 10.1186/s12943-017-0634-7.
• [5] De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217-21. doi: 10.1038/nature12439. Epub 2013 Aug 11.
• [6] Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations. Am J Med Genet A. 2018 Nov;176(11):2470-2478. doi: 10.1002/ajmg.a.40357. Epub 2018 Sep 23.
• [7] The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis.Hepatology. 2017 May;65(5):1492-1511. doi: 10.1002/hep.28971. Epub 2017 Mar 22.
• [8] TRIM8 downregulation in glioma affects cell proliferation and it is associated with patients survival.BMC Cancer. 2015 Jun 16;15:470. doi: 10.1186/s12885-015-1449-9.
• [9] Tripartite Motif 8 (TRIM8) Positively Regulates Pro-inflammatory Responses in Pseudomonas aeruginosa-Induced Keratitis Through Promoting K63-Linked Polyubiquitination of TAK1 Protein.Inflammation. 2017 Apr;40(2):454-463. doi: 10.1007/s10753-016-0491-3.
• [10] Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.Nat Genet. 2013 Apr;45(4):385-91, 391e1-2. doi: 10.1038/ng.2560.
• [11] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [12] miR-182 promotes tumor growth and increases chemoresistance of human anaplastic thyroid cancer by targeting tripartite motif 8.Onco Targets Ther. 2017 Feb 24;10:1115-1122. doi: 10.2147/OTT.S110468. eCollection 2017.
• [13] 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.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [21] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [22] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [25] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [26] 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.
• [27] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.