Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7OIIRH)

• DOT Name: E3 ubiquitin-protein ligase TRIM58 (TRIM58)
• Synonyms: EC 2.3.2.27; Protein BIA2; RING-type E3 ubiquitin transferase TRIM58; Tripartite motif-containing protein 58
• Gene Name: TRIM58
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Gastric cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Neoplasm
  Stomach cancer
  Ulcerative colitis
• UniProt ID: TRI58_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MAWAPPGERLREDARCPVCLDFLQEPVSVDCGHSFCLRCISEFCEKSDGAQGGVYACPQC
  RGPFRPSGFRPNRQLAGLVESVRRLGLGAGPGARRCARHGEDLSRFCEEDEAALCWVCDA
  GPEHRTHRTAPLQEAAGSYQVKLQMALELMRKELEDALTQEANVGKKTVIWKEKVEMQRQ
  RFRLEFEKHRGFLAQEEQRQLRRLEAEERATLQRLRESKSRLVQQSKALKELADELQERC
  QRPALGLLEGVRGVLSRSKAVTRLEAENIPMELKTACCIPGRRELLRKFQVDVKLDPATA
  HPSLLLTADLRSVQDGEPWRDVPNNPERFDTWPCILGLQSFSSGRHYWEVLVGEGAEWGL
  GVCQDTLPRKGETTPSPENGVWALWLLKGNEYMVLASPSVPLLQLESPRCIGIFLDYEAG
  EISFYNVTDGSYIYTFNQLFSGLLRPYFFICDATPLILPPTTIAGSGNWASRDHLDPASD
  VRDDHL
• Function: E3 ubiquitin ligase induced during late erythropoiesis. Directly binds and ubiquitinates the intermediate chain of the microtubule motor dynein (DYNC1LI1/DYNC1LI2), stimulating the degradation of the dynein holoprotein complex. May participate in the erythroblast enucleation process through regulation of nuclear polarization.
• Tissue Specificity: Expressed in erythroblasts.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Posttranslational Modification	[3]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[4]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of E3 ubiquitin-protein ligase TRIM58 (TRIM58).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase TRIM58 (TRIM58).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase TRIM58 (TRIM58).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase TRIM58 (TRIM58).	[10]

References

• [1] Downregulation of TRIM58 expression is associated with a poor patient outcome and enhances colorectal cancer cell invasion.Oncol Rep. 2018 Sep;40(3):1251-1260. doi: 10.3892/or.2018.6525. Epub 2018 Jun 26.
• [2] TRIM58 suppresses the tumor growth in gastric cancer by inactivation of -catenin signaling via ubiquitination.Cancer Biol Ther. 2020;21(3):203-212. doi: 10.1080/15384047.2019.1679554. Epub 2019 Nov 21.
• [3] Frequent silencing of the candidate tumor suppressor TRIM58 by promoter methylation in early-stage lung adenocarcinoma.Oncotarget. 2017 Jan 10;8(2):2890-2905. doi: 10.18632/oncotarget.13761.
• [4] TRIM58/cg26157385 methylation is associated with eight prognostic genes in lung squamous cell carcinoma.Oncol Rep. 2018 Jul;40(1):206-216. doi: 10.3892/or.2018.6426. Epub 2018 May 8.
• [5] Novel methylation-driven genes identified as prognostic indicators for lung squamous cell carcinoma.Am J Transl Res. 2019 Apr 15;11(4):1997-2012. eCollection 2019.
• [6] TRIM58 Restrains Intestinal Mucosal Inflammation by Negatively Regulating TLR2 in Myeloid Cells.J Immunol. 2019 Sep 15;203(6):1636-1649. doi: 10.4049/jimmunol.1900413. Epub 2019 Aug 5.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.