Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTGP4OK)

• DOT Name: E3 ubiquitin-protein ligase HECTD3 (HECTD3)
• Synonyms: EC 2.3.2.26; HECT domain-containing protein 3; HECT-type E3 ubiquitin transferase HECTD3
• Gene Name: HECTD3
• Related Disease:
  Advanced cancer
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Acute myelogenous leukaemia
  Bacterial infection
  Nervous system inflammation
• UniProt ID: HECD3_HUMAN
• EC Number: 2.3.2.26
• Pfam ID: PF03256 ; PF00632
• Sequence:
  MAGPGPGAVLESPRQLLGRVRFLAEAARSLRAGRPLPAALAFVPREVLYKLYKDPAGPSR
  VLLPVWEAEGLGLRVGAAGPAPGTGSGPLRAARDSIELRRGACVRTTGEELCNGHGLWVK
  LTKEQLAEHLGDCGLQEGWLLVCRPAEGGARLVPIDTPNHLQRQQQLFGVDYRPVLRWEQ
  VVDLTYSHRLGSRPQPAEAYAEAVQRLLYVPPTWTYECDEDLIHFLYDHLGKEDENLGSV
  KQYVESIDVSSYTEEFNVSCLTDSNADTYWESDGSQCQHWVRLTMKKGTIVKKLLLTVDT
  TDDNFMPKRVVVYGGEGDNLKKLSDVSIDETLIGDVCVLEDMTVHLPIIEIRIVECRDDG
  IDVRLRGVKIKSSRQRELGLNADLFQPTSLVRYPRLEGTDPEVLYRRAVLLQRFIKILDS
  VLHHLVPAWDHTLGTFSEIKQVKQFLLLSRQRPGLVAQCLRDSESSKPSFMPRLYINRRL
  AMEHRACPSRDPACKNAVFTQVYEGLKPSDKYEKPLDYRWPMRYDQWWECKFIAEGIIDQ
  GGGFRDSLADMSEELCPSSADTPVPLPFFVRTANQGNGTGEARDMYVPNPSCRDFAKYEW
  IGQLMGAALRGKEFLVLALPGFVWKQLSGEEVSWSKDFPAVDSVLVKLLEVMEGMDKETF
  EFKFGKELTFTTVLSDQQVVELIPGGAGIVVGYGDRSRFIQLVQKARLEESKEQVAAMQA
  GLLKVVPQAVLDLLTWQELEKKVCGDPEVTVDALRKLTRFEDFEPSDSRVQYFWEALNNF
  TNEDRSRFLRFVTGRSRLPARIYIYPDKLGYETTDALPESSTCSSTLFLPHYASAKVCEE
  KLRYAAYNCVAIDTDMSPWEE
• Function: E3 ubiquitin ligases accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates ubiquitination of TRIOBP and its subsequent proteasomal degradation, thus facilitating cell cycle progression by regulating the turn-over of TRIOBP. Mediates also ubiquitination of STX8.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[5]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of E3 ubiquitin-protein ligase HECTD3 (HECTD3).	[12]

References

• [1] The role of E3 ubiquitin ligase HECTD3 in cancer and beyond.Cell Mol Life Sci. 2020 Apr;77(8):1483-1495. doi: 10.1007/s00018-019-03339-3. Epub 2019 Oct 21.
• [2] Down-regulation of HECTD3 by HER2 inhibition makes serous ovarian cancer cells sensitive to platinum treatment.Cancer Lett. 2017 Dec 28;411:65-73. doi: 10.1016/j.canlet.2017.09.048. Epub 2017 Oct 6.
• [3] The E3 ligase HECTD3 promotes esophageal squamous cell carcinoma (ESCC) growth and cell survival through targeting and inhibiting caspase-9 activation.Cancer Lett. 2017 Sep 28;404:44-52. doi: 10.1016/j.canlet.2017.07.004. Epub 2017 Jul 15.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection.J Clin Invest. 2018 Aug 31;128(9):4148-4162. doi: 10.1172/JCI120406. Epub 2018 Jul 30.
• [6] Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation.Nat Commun. 2019 Feb 11;10(1):701. doi: 10.1038/s41467-019-08605-3.
• [7] 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.
• [8] 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.
• [9] 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.
• [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.
• [11] 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.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.