Details of Drug Off-Target (DOT)

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

• DOT Name: Tripartite motif-containing protein 16 (TRIM16)
• Synonyms: EC 2.3.2.27; E3 ubiquitin-protein ligase TRIM16; Estrogen-responsive B box protein
• Gene Name: TRIM16
• Related Disease:
  Skin cancer
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Neoplasm
  Neuroblastoma
  Non-small-cell lung cancer
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Promyelocytic leukaemia
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Pulmonary fibrosis
  Stomach cancer
  Tuberculosis
  Breast cancer
  Breast carcinoma
  Carcinoma
  Metastatic malignant neoplasm
  Advanced cancer
  Cutaneous squamous cell carcinoma
  Melanoma
• UniProt ID: TRI16_HUMAN
• PDB ID: 7QS3
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643
• Sequence:
  MAELDLMAPGPLPRATAQPPAPLSPDSGSPSPDSGSASPVEEEDVGSSEKLGRETEEQDS
  DSAEQGDPAGEGKEVLCDFCLDDTRRVKAVKSCLTCMVNYCEEHLQPHQVNIKLQSHLLT
  EPVKDHNWRYCPAHHSPLSAFCCPDQQCICQDCCQEHSGHTIVSLDAARRDKEAELQCTQ
  LDLERKLKLNENAISRLQANQKSVLVSVSEVKAVAEMQFGELLAAVRKAQANVMLFLEEK
  EQAALSQANGIKAHLEYRSAEMEKSKQELERMAAISNTVQFLEEYCKFKNTEDITFPSVY
  VGLKDKLSGIRKVITESTVHLIQLLENYKKKLQEFSKEEEYDIRTQVSAVVQRKYWTSKP
  EPSTREQFLQYAYDITFDPDTAHKYLRLQEENRKVTNTTPWEHPYPDLPSRFLHWRQVLS
  QQSLYLHRYYFEVEIFGAGTYVGLTCKGIDRKGEERNSCISGNNFSWSLQWNGKEFTAWY
  SDMETPLKAGPFRRLGVYIDFPGGILSFYGVEYDTMTLVHKFACKFSEPVYAAFWLSKKE
  NAIRIVDLGEEPEKPAPSLVGTAP
• Function: E3 ubiquitin ligase that plays an essential role in the organization of autophagic response and ubiquitination upon lysosomal and phagosomal damages. Plays a role in the stress-induced biogenesis and degradation of protein aggresomes by regulating the p62-KEAP1-NRF2 signaling and particularly by modulating the ubiquitination levels and thus stability of NRF2. Acts as a scaffold protein and facilitates autophagic degradation of protein aggregates by interacting with p62/SQSTM, ATG16L1 and LC3B/MAP1LC3B. In turn, protects the cell against oxidative stress-induced cell death as a consequence of endomembrane damage.
• Tissue Specificity: Highest levels found in testis, ovary, small intestine, colon, placenta, heart, skeletal muscle and mammary gland. More highly expressed in the fetus than in the corresponding adult tissues. Expressed in basal keratinocytes.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Skin cancer	DISTM18U	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Osteoporosis	DISF2JE0	Strong	Biomarker	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[9]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[10]
Pulmonary fibrosis	DISQKVLA	Strong	Genetic Variation	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[12]
Breast cancer	DIS7DPX1	moderate	Biomarker	[6]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[6]
Carcinoma	DISH9F1N	moderate	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[14]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[15]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[16]
Melanoma	DIS1RRCY	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[22]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[23]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Tripartite motif-containing protein 16 (TRIM16).	[24]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[25]
Penicillin V	DMKVOYF	Approved	Penicillin V increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[25]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[26]
Benzylpenicillin	DMS9503	Phase 3	Benzylpenicillin increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[28]
T83193	DMHO29Y	Patented	T83193 increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tripartite motif-containing protein 16 (TRIM16).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[30]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Tripartite motif-containing protein 16 (TRIM16).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Tripartite motif-containing protein 16 (TRIM16).	[27]

References

• [1] Heterozygous loss of keratinocyte TRIM16 expression increases melanocytic cell lesions and lymph node metastasis.J Cancer Res Clin Oncol. 2019 Sep;145(9):2241-2250. doi: 10.1007/s00432-019-02981-5. Epub 2019 Jul 24.
• [2] Tripartite Motif 16 Inhibits the Migration and Invasion in Ovarian Cancer Cells.Oncol Res. 2017 Apr 14;25(4):551-558. doi: 10.3727/096504016X14758370595285. Epub 2016 Oct 12.
• [3] RASSF6-TRIM16 axis promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma.J Genet Genomics. 2019 Oct 20;46(10):477-488. doi: 10.1016/j.jgg.2019.10.004. Epub 2019 Nov 14.
• [4] Long noncoding ribonucleic acid specific for distant metastasis of gastric cancer is associated with TRIM16 expression and facilitates tumor cell invasion in vitro.J Gastroenterol Hepatol. 2015 Sep;30(9):1367-75. doi: 10.1111/jgh.12976.
• [5] Tripartite motif 16 inhibits hepatocellular carcinoma cell migration and invasion.Int J Oncol. 2016 Apr;48(4):1639-49. doi: 10.3892/ijo.2016.3398. Epub 2016 Feb 17.
• [6] High TDP43 expression is required for TRIM16-induced inhibition of cancer cell growth and correlated with good prognosis of neuroblastoma and breast cancer patients.Cancer Lett. 2016 May 1;374(2):315-23. doi: 10.1016/j.canlet.2016.02.021. Epub 2016 Feb 20.
• [7] Downregulation of MicroRNA-135 Promotes Sensitivity of Non-Small Cell Lung Cancer to Gefitinib by Targeting TRIM16.Oncol Res. 2018 Aug 23;26(7):1005-1014. doi: 10.3727/096504017X15144755633680. Epub 2018 Jan 2.
• [8] Galectin-3 and TRIM16 coregulate osteogenic differentiation of human bone marrow-derived mesenchymal stem cells at least partly via enhancing autophagy.Bone. 2020 Feb;131:115059. doi: 10.1016/j.bone.2019.115059. Epub 2019 Sep 12.
• [9] The estrogen-responsive B box protein is a novel regulator of the retinoid signal.J Biol Chem. 2006 Jun 30;281(26):18246-56. doi: 10.1074/jbc.M600879200. Epub 2006 Apr 24.
• [10] TRIM16 suppresses the progression of prostate tumors by inhibiting the Snail signaling pathway.Int J Mol Med. 2016 Dec;38(6):1734-1742. doi: 10.3892/ijmm.2016.2774. Epub 2016 Oct 17.
• [11] Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced pulmonary fibrosis in mice.PLoS Genet. 2013;9(1):e1003203. doi: 10.1371/journal.pgen.1003203. Epub 2013 Jan 17.
• [12] Galectins and TRIMs directly interact and orchestrate autophagic response to endomembrane damage.Autophagy. 2017 Jun 3;13(6):1086-1087. doi: 10.1080/15548627.2017.1307487. Epub 2017 Apr 3.
• [13] Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli-1 degradation via the ubiquitin-proteasome pathway.Oncol Rep. 2016 Feb;35(2):1204-12. doi: 10.3892/or.2015.4437. Epub 2015 Nov 18.
• [14] Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells.Biochem Biophys Res Commun. 2015 May 15;460(4):1021-8. doi: 10.1016/j.bbrc.2015.03.144. Epub 2015 Apr 2.
• [15] TRIM16 governs the biogenesis and disposal of stress-induced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer.Autophagy. 2019 May;15(5):924-926. doi: 10.1080/15548627.2019.1586251. Epub 2019 Mar 5.
• [16] TRIM16 inhibits proliferation and migration through regulation of interferon beta 1 in melanoma cells.Oncotarget. 2014 Oct 30;5(20):10127-39. doi: 10.18632/oncotarget.2466.
• [17] 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.
• [18] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [19] 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.
• [20] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [21] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [24] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [25] Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells. Toxicol Appl Pharmacol. 2012 Aug 1;262(3):283-92.
• [26] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [27] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [29] Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res. 2007 Mar 1;616(1-2):60-9. doi: 10.1016/j.mrfmmm.2006.11.022. Epub 2006 Dec 18.
• [30] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.