Details of Drug Off-Target (DOT)

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

DOT Name E3 ubiquitin-protein ligase HACE1 (HACE1)
Synonyms EC 2.3.2.26; HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase 1; HECT-type E3 ubiquitin transferase HACE1
Gene Name HACE1
Related Disease
Melanoma ( )
Adult lymphoma ( )
Advanced cancer ( )
B-cell neoplasm ( )
Bone osteosarcoma ( )
Burkitt lymphoma ( )
Carcinoma of liver and intrahepatic biliary tract ( )
Huntington disease ( )
Liver cancer ( )
Lymphoma ( )
Multiple sclerosis ( )
Neuroblastoma ( )
Neurodevelopmental disorder ( )
Osteosarcoma ( )
Pediatric lymphoma ( )
Spastic paraplegia-severe developmental delay-epilepsy syndrome ( )
Wilms tumor ( )
Breast cancer ( )
Breast carcinoma ( )
Carcinoma ( )
Childhood kidney Wilms tumor ( )
Colorectal carcinoma ( )
Gastric cancer ( )
Stomach cancer ( )
UniProt ID
HACE1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
8H8X; 8HAE
EC Number
2.3.2.26
Pfam ID
PF12796 ; PF13637 ; PF00632
Sequence
MERAMEQLNRLTRSLRRARTVELPEDNETAVYTLMPMVMADQHRSVSELLSNSKFDVNYA
FGRVKRSLLHIAANCGSVECLVLLLKKGANPNYQDISGCTPLHLAARNGQKKCMSKLLEY
SADVNICNNEGLTAIHWLAVNGRTELLHDLVQHVSDVDVEDAMGQTALHVACQNGHKTTV
QCLLDSGADINRPNVSGATPLYFACSHGQRDTAQILLLRGAKYLPDKNGVTPLDLCVQGG
YGETCEVLIQYHPRLFQTIIQMTQNEDLRENMLRQVLEHLSQQSESQYLKILTSLAEVAT
TNGHKLLSLSSNYDAQMKSLLRIVRMFCHVFRIGPSSPSNGIDMGYNGNKTPRSQVFKPL
ELLWHSLDEWLVLIATELMKNKRDSTEITSILLKQKGQDQDAASIPPFEPPGPGSYENLS
TGTRESKPDALAGRQEASADCQDVISMTANRLSAVIQAFYMCCSCQMPPGMTSPRFIEFV
CKHDEVLKCFVNRNPKIIFDHFHFLLECPELMSRFMHIIKAQPFKDRCEWFYEHLHSGQP
DSDMVHRPVNENDILLVHRDSIFRSSCEVVSKANCAKLKQGIAVRFHGEEGMGQGVVREW
FDILSNEIVNPDYALFTQSADGTTFQPNSNSYVNPDHLNYFRFAGQILGLALNHRQLVNI
YFTRSFYKHILGIPVNYQDVASIDPEYAKNLQWILDNDISDLGLELTFSVETDVFGAMEE
VPLKPGGGSILVTQNNKAEYVQLVTELRMTRAIQPQINAFLQGFHMFIPPSLIQLFDEYE
LELLLSGMPEIDVSDWIKNTEYTSGYEREDPVIQWFWEVVEDITQEERVLLLQFVTGSSR
VPHGGFANIMGGSGLQNFTIAAVPYTPNLLPTSSTCINMLKLPEYPSKEILKDRLLVALH
CGSYGYTMA
Function
E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases. Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion. Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after cell division. Specifically interacts with GTP-bound RAC1, mediating ubiquitination and subsequent degradation of active RAC1, thereby playing a role in host defense against pathogens. May also act as a transcription regulator via its interaction with RARB.
Tissue Specificity Expressed in multiple tissues including heart, brain and kidney.
Reactome Pathway
Antigen processing (R-HSA-983168 )

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Melanoma DIS1RRCY Definitive Biomarker [1]
Adult lymphoma DISK8IZR Strong Altered Expression [2]
Advanced cancer DISAT1Z9 Strong Biomarker [3]
B-cell neoplasm DISVY326 Strong Biomarker [4]
Bone osteosarcoma DIST1004 Strong Altered Expression [5]
Burkitt lymphoma DIS9D5XU Strong Altered Expression [2]
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W Strong Biomarker [6]
Huntington disease DISQPLA4 Strong Biomarker [7]
Liver cancer DISDE4BI Strong Biomarker [6]
Lymphoma DISN6V4S Strong Altered Expression [2]
Multiple sclerosis DISB2WZI Strong Genetic Variation [8]
Neuroblastoma DISVZBI4 Strong Biomarker [9]
Neurodevelopmental disorder DIS372XH Strong Genetic Variation [10]
Osteosarcoma DISLQ7E2 Strong Altered Expression [5]
Pediatric lymphoma DIS51BK2 Strong Altered Expression [2]
Spastic paraplegia-severe developmental delay-epilepsy syndrome DIS15YI9 Strong Autosomal recessive [10]
Wilms tumor DISB6T16 Strong Genetic Variation [11]
Breast cancer DIS7DPX1 moderate Biomarker [12]
Breast carcinoma DIS2UE88 moderate Biomarker [12]
Carcinoma DISH9F1N moderate Posttranslational Modification [13]
Childhood kidney Wilms tumor DIS0NMK3 Limited Genetic Variation [11]
Colorectal carcinoma DIS5PYL0 Limited Biomarker [14]
Gastric cancer DISXGOUK Limited Altered Expression [15]
Stomach cancer DISKIJSX Limited Altered Expression [15]
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⏷ Show the Full List of 24 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 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 HACE1 (HACE1). [16]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of E3 ubiquitin-protein ligase HACE1 (HACE1). [17]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase HACE1 (HACE1). [18]
Indomethacin DMSC4A7 Approved Indomethacin decreases the expression of E3 ubiquitin-protein ligase HACE1 (HACE1). [19]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of E3 ubiquitin-protein ligase HACE1 (HACE1). [22]
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2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase HACE1 (HACE1). [20]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase HACE1 (HACE1). [21]
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References

1 Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells.Cell Death Differ. 2018 Nov;25(11):2010-2022. doi: 10.1038/s41418-018-0090-y. Epub 2018 Mar 7.
2 Heterogeneous epigenetic regulation of HACE1 in Burkitt- Lymphoma-derived cells.Leuk Res. 2017 Sep;60:53-57. doi: 10.1016/j.leukres.2017.06.006. Epub 2017 Jun 16.
3 Loss of the Tumor Suppressor HACE1 Contributes to Cancer Progression.Curr Drug Targets. 2019;20(10):1018-1028. doi: 10.2174/1389450120666190227184654.
4 HACE1 is a putative tumor suppressor gene in B-cell lymphomagenesis and is down-regulated by both deletion and epigenetic alterations.Leuk Res. 2016 Jun;45:90-100. doi: 10.1016/j.leukres.2016.04.007. Epub 2016 Apr 11.
5 HACE1 is a potential tumor suppressor in osteosarcoma.Cell Death Dis. 2019 Jan 8;10(1):21. doi: 10.1038/s41419-018-1276-4.
6 Demethylation of the HACE1 gene promoter inhibits the proliferation of human liver cancer cells.Oncol Lett. 2019 May;17(5):4361-4368. doi: 10.3892/ol.2019.10139. Epub 2019 Mar 12.
7 HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo.Hum Mol Genet. 2018 Jan 15;27(2):239-253. doi: 10.1093/hmg/ddx394.
8 A genome-wide association study of brain lesion distribution in multiple sclerosis.Brain. 2013 Apr;136(Pt 4):1012-24. doi: 10.1093/brain/aws363. Epub 2013 Feb 13.
9 Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma.Nat Genet. 2012 Oct;44(10):1126-30. doi: 10.1038/ng.2387. Epub 2012 Sep 2.
10 HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803. doi: 10.1136/jmedgenet-2015-103344. Epub 2015 Sep 30.
11 Association Between HACE1 Gene Polymorphisms and Wilms' Tumor Risk in a Chinese Population.Cancer Invest. 2017 Nov 26;35(10):633-638. doi: 10.1080/07357907.2017.1405016.
12 Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells.Oncogene. 2019 May;38(19):3651-3666. doi: 10.1038/s41388-019-0676-y. Epub 2019 Jan 18.
13 Methylation of HACE1 in gastric carcinoma.Anticancer Res. 2009 Jun;29(6):2231-3.
14 Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1.J Cell Physiol. 2019 Jun;234(6):9663-9672. doi: 10.1002/jcp.27653. Epub 2018 Oct 26.
15 Overexpression of HACE1 in gastric cancer inhibits tumor aggressiveness by impeding cell proliferation and migration.Cancer Med. 2018 Jun;7(6):2472-2484. doi: 10.1002/cam4.1496. Epub 2018 Apr 19.
16 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
17 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
18 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
19 Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
20 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.
21 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
22 Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.