Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15YO6N)

• DOT Name: E3 ubiquitin-protein ligase TRIM62 (TRIM62)
• Synonyms: EC 2.3.2.27; Tripartite motif-containing protein 62
• Gene Name: TRIM62
• Related Disease:
  Acute myelogenous leukaemia
  Acute undifferentiated leukemia
  Breast cancer
  Breast neoplasm
  Ductal breast carcinoma in situ
  Epithelial neoplasm
  Invasive breast carcinoma
  leukaemia
  Leukemia
  Neoplasm
  Cervical cancer
  Cervical carcinoma
  Metastatic malignant neoplasm
  Breast carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: TRI62_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13765 ; PF00622 ; PF00643 ; PF15227
• Sequence:
  MACSLKDELLCSICLSIYQDPVSLGCEHYFCRRCITEHWVRQEAQGARDCPECRRTFAEP
  ALAPSLKLANIVERYSSFPLDAILNARRAARPCQAHDKVKLFCLTDRALLCFFCDEPALH
  EQHQVTGIDDAFDELQRELKDQLQALQDSEREHTEALQLLKRQLAETKSSTKSLRTTIGE
  AFERLHRLLRERQKAMLEELEADTARTLTDIEQKVQRYSQQLRKVQEGAQILQERLAETD
  RHTFLAGVASLSERLKGKIHETNLTYEDFPTSKYTGPLQYTIWKSLFQDIHPVPAALTLD
  PGTAHQRLILSDDCTIVAYGNLHPQPLQDSPKRFDVEVSVLGSEAFSSGVHYWEVVVAEK
  TQWVIGLAHEAASRKGSIQIQPSRGFYCIVMHDGNQYSACTEPWTRLNVRDKLDKVGVFL
  DYDQGLLIFYNADDMSWLYTFREKFPGKLCSYFSPGQSHANGKNVQPLRINTVRI
• Function: E3 ubiquitin ligase that plays a role in antifungal immunity by mediating 'Lys-27'-linked ubiquitination of CARD9 downstream of C-type lectin receptors; leading to CARD9 activation, followed by activation of NF-kappa-B and MAP kinase p38 pathways. E3 ubiquitin ligase activity is dependent on E2 ubiquitin-conjugating enzyme UBE2D2.
• Reactome Pathway: Interferon gamma signaling (R-HSA-877300)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Acute undifferentiated leukemia	DISJ4SSG	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[4]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[3]
Invasive breast carcinoma	DISANYTW	Strong	Genetic Variation	[4]
leukaemia	DISS7D1V	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Cervical cancer	DISFSHPF	moderate	Altered Expression	[5]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[5]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Lung cancer	DISCM4YA	Limited	Altered Expression	[2]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorafenib	DMS8IFC	Approved	E3 ubiquitin-protein ligase TRIM62 (TRIM62) affects the response to substance of Sorafenib.	[18]

10 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 E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase TRIM62 (TRIM62).	[12]

References

• [1] Loss of TRIM62 expression is an independent adverse prognostic factor in acute myeloid leukemia.Clin Lymphoma Myeloma Leuk. 2015 Feb;15(2):115-127.e15. doi: 10.1016/j.clml.2014.07.011. Epub 2014 Aug 12.
• [2] Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer.J Pathol. 2014 Sep;234(1):108-19. doi: 10.1002/path.4385. Epub 2014 Jul 16.
• [3] DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity.Cancer Res. 2014 Oct 15;74(20):5683-9. doi: 10.1158/0008-5472.CAN-14-1171. Epub 2014 Sep 26.
• [4] DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.PLoS Med. 2009 May 26;6(5):e1000068. doi: 10.1371/journal.pmed.1000068. Epub 2009 May 5.
• [5] Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer.J Exp Clin Cancer Res. 2016 Oct 28;35(1):170. doi: 10.1186/s13046-016-0445-5.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] 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.
• [10] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] TRIM62 silencing represses the proliferation and invasion and increases the chemosensitivity of hepatocellular carcinoma cells by affecting the NF-B pathway. Toxicol Appl Pharmacol. 2022 Jun 15;445:116035. doi: 10.1016/j.taap.2022.116035. Epub 2022 Apr 23.