Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLQKUG0)

• DOT Name: Tripartite motif-containing protein 14 (TRIM14)
• Gene Name: TRIM14
• Related Disease:
  Adult glioblastoma
  Arteriosclerosis
  Atherosclerosis
  Bone cancer
  Bone osteosarcoma
  Glioblastoma multiforme
  Glioma
  Hepatitis C virus infection
  Herpes simplex infection
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Thyroid gland papillary carcinoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Influenza
  Hepatocellular carcinoma
  Advanced cancer
  Gastric cancer
  Squamous cell carcinoma
  Stomach cancer
• UniProt ID: TRI14_HUMAN
• PDB ID: 6JBM
• Pfam ID: PF13765 ; PF00622 ; PF00643
• Sequence:
  MAGAATGSRTPGRSELVEGCGWRCPEHGDRVAELFCRRCRRCVCALCPVLGAHRGHPVGL
  ALEAAVHVQKLSQECLKQLAIKKQQHIDNITQIEDATEKLKANAESSKTWLKGKFTELRL
  LLDEEEALAKKFIDKNTQLTLQVYREQADSCREQLDIMNDLSNRVWSISQEPDPVQRLQA
  YTATEQEMQQQMSLGELCHPVPLSFEPVKSFFKGLVEAVESTLQTPLDIRLKESINCQLS
  DPSSTKPGTLLKTSPSPERSLLLKYARTPTLDPDTMHARLRLSADRLTVRCGLLGSLGPV
  PVLRFDALWQVLARDCFATGRHYWEVDVQEAGAGWWVGAAYASLRRRGASAAARLGCNRQ
  SWCLKRYDLEYWAFHDGQRSRLRPRDDLDRLGVFLDYEAGVLAFYDVTGGMSHLHTFRAT
  FQEPLYPALRLWEGAISIPRLP
• Function: Plays an essential role in the innate immune defense against viruses and bacteria. Promotes the 'Lys-48'-linked ubiquitination and subsequent degradation of hepatitis C virus NS5A leading to the inhibition of viral replication. Plays also a role in the inhibition of ebolavirus infection by enhancing IFN-beta and NF-kappa-B activation after binding to the viral protein NP. Facilitates the type I IFN response by interacting with MAVS at the outer mitochondria membrane and thereby recruiting NF-kappa-B essential modulator IKBKG/NEMO to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3/IRF3 and NF-kappa-B pathways. Positively regulates the CGAS-induced type I interferon signaling pathway by stabilizing CGAS and inhibiting its autophagic degradation. Acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 and resolve interferon-stimulated gene (ISG) expression. Inhibits the transcriptional activity of SPI1 in a dose-dependent manner. Inhibits also OPTN-mediated selective autophagic degradation of KDM4D and thereby negatively regulates H3K9me2 and H3K9me3. Mechanistically, recruits USP14 to remove the 'Lys-63'-linked ubiquitination of KDM4D, preventing its recognition by OPTN and subsequent degradation.
• Tissue Specificity: Highest expression in liver; undetectable in skeletal muscle.
• 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
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Bone cancer	DIS38NA0	Strong	Altered Expression	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[10]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[11]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[12]
Influenza	DIS3PNU3	moderate	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Disputed	Altered Expression	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Gastric cancer	DISXGOUK	Limited	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[15]
Stomach cancer	DISKIJSX	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tripartite motif-containing protein 14 (TRIM14).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[25]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tripartite motif-containing protein 14 (TRIM14).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[24]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tripartite motif-containing protein 14 (TRIM14).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Tripartite motif-containing protein 14 (TRIM14).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tripartite motif-containing protein 14 (TRIM14).	[29]

References

• [1] Tripartite motif-containing 14 (TRIM14) promotes epithelial-mesenchymal transition via ZEB2 in glioblastoma cells.J Exp Clin Cancer Res. 2019 Feb 6;38(1):57. doi: 10.1186/s13046-019-1070-x.
• [2] TRIM14 promotes endothelial activation via activating NF-B signaling pathway.J Mol Cell Biol. 2020 Apr 24;12(3):176-189. doi: 10.1093/jmcb/mjz040.
• [3] Bispecific antibody suppresses osteosarcoma aggressiveness through regulation of NF-B signaling pathway.Tumour Biol. 2017 Jun;39(6):1010428317705572. doi: 10.1177/1010428317705572.
• [4] Target therapy of TRIM-14 inhibits osteosarcoma aggressiveness through the nuclear factor-B signaling pathway.Exp Ther Med. 2018 Mar;15(3):2365-2373. doi: 10.3892/etm.2017.5679. Epub 2017 Dec 27.
• [5] TRIM14 promotes chemoresistance in gliomas by activating Wnt/-catenin signaling via stabilizing Dvl2.Oncogene. 2018 Oct;37(40):5403-5415. doi: 10.1038/s41388-018-0344-7. Epub 2018 Jun 4.
• [6] TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein.Sci Rep. 2016 Aug 31;6:32336. doi: 10.1038/srep32336.
• [7] TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses.Mol Cell. 2016 Oct 6;64(1):105-119. doi: 10.1016/j.molcel.2016.08.025. Epub 2016 Sep 22.
• [8] High Levels of TRIM14 Are Associated with Poor Prognosis in Hepatocellular Carcinoma.Oncol Res Treat. 2018;41(3):129-134. doi: 10.1159/000485625. Epub 2018 Feb 27.
• [9] TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer.Sci Rep. 2017 Jan 6;7:39692. doi: 10.1038/srep39692.
• [10] Tripartite motif containing 14: An oncogene in papillary thyroid carcinoma.Biochem Biophys Res Commun. 2020 Jan 8;521(2):360-367. doi: 10.1016/j.bbrc.2019.10.127. Epub 2019 Oct 24.
• [11] TRIM14 Promotes Breast Cancer Cell Proliferation by Inhibiting Apoptosis.Oncol Res. 2019 Mar 29;27(4):439-447. doi: 10.3727/096504018X15214994641786. Epub 2018 Mar 21.
• [12] TRIM14 promotes cell proliferation and inhibits apoptosis by suppressing PTEN in colorectal cancer.Cancer Manag Res. 2019 Jun 24;11:5725-5735. doi: 10.2147/CMAR.S210782. eCollection 2019.
• [13] Inhibition of Influenza A Virus Replication by TRIM14 via Its Multifaceted Protein-Protein Interaction With NP.Front Microbiol. 2019 Feb 26;10:344. doi: 10.3389/fmicb.2019.00344. eCollection 2019.
• [14] TRIM14 promotes the migration and invasion of gastric cancer by regulating epithelialtomesenchymal transition via activation of AKT signaling regulated by miR?95?p.Oncol Rep. 2018 Dec;40(6):3273-3284. doi: 10.3892/or.2018.6750. Epub 2018 Sep 28.
• [15] miR-15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer.Oncol Rep. 2017 May;37(5):2720-2726. doi: 10.3892/or.2017.5532. Epub 2017 Mar 27.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] 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.
• [24] 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.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] 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.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [29] 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.
• [30] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [31] 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.
• [32] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.