Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU4DSDE)

DOT Name Probable E3 ubiquitin-protein ligase HERC4 (HERC4)
Synonyms EC 2.3.2.26; HECT domain and RCC1-like domain-containing protein 4; HECT-type E3 ubiquitin transferase HERC4
Gene Name HERC4
Related Disease
Advanced cancer ( )
Lung cancer ( )
Lung carcinoma ( )
Non-small-cell lung cancer ( )
Hepatocellular carcinoma ( )
Breast cancer ( )
Breast carcinoma ( )
Hereditary hemochromatosis ( )
Neoplasm ( )
UniProt ID
HERC4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.3.2.26
Pfam ID
PF00632 ; PF00415
Sequence
MLCWGNASFGQLGLGGIDEEIVLEPRKSDFFINKRVRDVGCGLRHTVFVLDDGTVYTCGC
NDLGQLGHEKSRKKPEQVVALDAQNIVAVSCGEAHTLALNDKGQVYAWGLDSDGQLGLVG
SEECIRVPRNIKSLSDIQIVQVACGYYHSLALSKASEVFCWGQNKYGQLGLGTDCKKQTS
PQLLKSLLGIPFMQVAAGGAHSFVLTLSGAIFGWGRNKFGQLGLNDENDRYVPNLLKSLR
SQKIVYICCGEDHTAALTKEGGVFTFGAGGYGQLGHNSTSHEINPRKVFELMGSIVTEIA
CGRQHTSAFVPSSGRIYSFGLGGNGQLGTGSTSNRKSPFTVKGNWYPYNGQCLPDIDSEE
YFCVKRIFSGGDQSFSHYSSPQNCGPPDDFRCPNPTKQIWTVNEALIQKWLSYPSGRFPV
EIANEIDGTFSSSGCLNGSFLAVSNDDHYRTGTRFSGVDMNAARLLFHKLIQPDHPQISQ
QVAASLEKNLIPKLTSSLPDVEALRFYLTLPECPLMSDSNNFTTIAIPFGTALVNLEKAP
LKVLENWWSVLEPPLFLKIVELFKEVVVHLLKLYKIGIPPSERRIFNSFLHTALKVLEIL
HRVNEKMGQIIQYDKFYIHEVQELIDIRNDYINWVQQQAYGMDVNHGLTELADIPVTICT
YPFVFDAQAKTTLLQTDAVLQMQMAIDQAHRQNVSSLFLPVIESVNPCLILVVRRENIVG
DAMEVLRKTKNIDYKKPLKVIFVGEDAVDAGGVRKEFFLLIMRELLDPKYGMFRYYEDSR
LIWFSDKTFEDSDLFHLIGVICGLAIYNCTIVDLHFPLALYKKLLKKKPSLDDLKELMPD
VGRSMQQLLDYPEDDIEETFCLNFTITVENFGATEVKELVLNGADTAVNKQNRQEFVDAY
VDYIFNKSVASLFDAFHAGFHKVCGGKVLLLFQPNELQAMVIGNTNYDWKELEKNTEYKG
EYWAEHPTIKIFWEVFHELPLEKKKQFLLFLTGSDRIPILGMKSLKLVIQSTGGGEEYLP
VSHTCFNLLDLPKYTEKETLRSKLIQAIDHNEGFSLI
Function
Probable E3 ubiquitin-protein ligase involved in either protein trafficking or in the distribution of cellular structures. Required for spermatozoon maturation and fertility, and for the removal of the cytoplasmic droplet of the spermatozoon. E3 ubiquitin-protein ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer it to targeted substrates.
Tissue Specificity Expressed in brain and testis and detected in heart and placenta.
KEGG Pathway
Ubiquitin mediated proteolysis (hsa04120 )
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]
Lung cancer DISCM4YA Strong Biomarker [1]
Lung carcinoma DISTR26C Strong Biomarker [1]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [2]
Hepatocellular carcinoma DIS0J828 moderate Biomarker [3]
Breast cancer DIS7DPX1 Limited Biomarker [4]
Breast carcinoma DIS2UE88 Limited Biomarker [4]
Hereditary hemochromatosis DISVG5MT Limited Biomarker [5]
Neoplasm DISZKGEW Limited Biomarker [4]
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⏷ Show the Full List of 9 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [6]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [7]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [8]
Temozolomide DMKECZD Approved Temozolomide decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [9]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [10]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [11]
Dasatinib DMJV2EK Approved Dasatinib decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [12]
Testosterone Undecanoate DMZO10Y Approved Testosterone Undecanoate decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [13]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [15]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [16]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [17]
Biotin DMKMCE1 Investigative Biotin increases the expression of Probable E3 ubiquitin-protein ligase HERC4 (HERC4). [18]
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⏷ Show the Full List of 12 Drug(s)

References

1 The Emerging Roles of the HERC Ubiquitin Ligases in Cancer.Curr Pharm Des. 2018;24(15):1676-1681. doi: 10.2174/1381612824666180528081024.
2 HERC4 exerts an anti-tumor role through destabilizing the oncoprotein Smo.Biochem Biophys Res Commun. 2019 Jun 11;513(4):1013-1018. doi: 10.1016/j.bbrc.2019.04.113. Epub 2019 Apr 19.
3 HERC4 Is Overexpressed in Hepatocellular Carcinoma and Contributes to the Proliferation and Migration of Hepatocellular Carcinoma Cells.DNA Cell Biol. 2017 Jun;36(6):490-500. doi: 10.1089/dna.2016.3626. Epub 2017 Apr 21.
4 A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1.Protein Cell. 2019 Aug;10(8):595-605. doi: 10.1007/s13238-019-0607-2. Epub 2019 Feb 1.
5 E3 ligase Herc4 regulates Hedgehog signalling through promoting Smoothened degradation.J Mol Cell Biol. 2019 Sep 19;11(9):791-803. doi: 10.1093/jmcb/mjz024.
6 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.
7 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.
8 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.
9 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
10 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
11 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
12 Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
13 Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
14 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
15 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
16 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.
17 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
18 Clusters of biotin-responsive genes in human peripheral blood mononuclear cells. J Nutr Biochem. 2004 Jul;15(7):433-9.