Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOKC2G5)

• DOT Name: EH domain-containing protein 3 (EHD3)
• Synonyms: PAST homolog 3
• Gene Name: EHD3
• Related Disease:
  Hepatocellular carcinoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Brain cancer
  Brain neoplasm
  Cardiac disease
  Cardiac failure
  Congestive heart failure
  Deafness
  Glioma
  Major depressive disorder
  Neoplasm
  Syphilis
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: EHD3_HUMAN
• Pfam ID: PF18150 ; PF00350 ; PF12763 ; PF16880
• Sequence:
  MFSWLGTDDRRRKDPEVFQTVSEGLKKLYKSKLLPLEEHYRFHEFHSPALEDADFDNKPM
  VLLVGQYSTGKTTFIRYLLEQDFPGMRIGPEPTTDSFIAVMQGDMEGIIPGNALVVDPKK
  PFRKLNAFGNAFLNRFVCAQLPNPVLESISVIDTPGILSGEKQRISRGYDFAAVLEWFAE
  RVDRIILLFDAHKLDISDEFSEVIKALKNHEDKMRVVLNKADQIETQQLMRVYGALMWSL
  GKIVNTPEVIRVYIGSFWSHPLLIPDNRKLFEAEEQDLFRDIQSLPRNAALRKLNDLIKR
  ARLAKVHAYIISSLKKEMPSVFGKDNKKKELVNNLAEIYGRIEREHQISPGDFPNLKRMQ
  DQLQAQDFSKFQPLKSKLLEVVDDMLAHDIAQLMVLVRQEESQRPIQMVKGGAFEGTLHG
  PFGHGYGEGAGEGIDDAEWVVARDKPMYDEIFYTLSPVDGKITGANAKKEMVRSKLPNSV
  LGKIWKLADIDKDGMLDDDEFALANHLIKVKLEGHELPNELPAHLLPPSKRKVAE
• Function: ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. In vitro causes tubulation of endocytic membranes. Binding to phosphatidic acid induces its membrane tubulation activity. Plays a role in endocytic transport. Involved in early endosome to recycling endosome compartment (ERC), retrograde early endosome to Golgi, and endosome to plasma membrane (rapid recycling) protein transport. Involved in the regulation of Golgi maintenance and morphology. Involved in the recycling of internalized D1 dopamine receptor. Plays a role in cardiac protein trafficking probably implicating ANK2. Involved in the ventricular membrane targeting of SLC8A1 and CACNA1C and probably the atrial membrane localization of CACNA1GG and CACNA1H implicated in the regulation of atrial myocyte excitability and cardiac conduction. In conjunction with EHD4 may be involved in endocytic trafficking of KDR/VEGFR2 implicated in control of glomerular function. Involved in the rapid recycling of integrin beta-3 implicated in cell adhesion maintenance. Involved in the unidirectional retrograde dendritic transport of endocytosed BACE1 and in efficient sorting of BACE1 to axons implicating a function in neuronal APP processing. Plays a role in the formation of the ciliary vesicle, an early step in cilium biogenesis; possibly sharing redundant functions with EHD1.
• Tissue Specificity: Highly expressed in heart and brain and moderately expressed in kidney, liver, and placenta.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Posttranslational Modification	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Brain cancer	DISBKFB7	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Deafness	DISKCLH4	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Syphilis	DISJ73BS	Strong	Biomarker	[8]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[9]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]

8 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 EH domain-containing protein 3 (EHD3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of EH domain-containing protein 3 (EHD3).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of EH domain-containing protein 3 (EHD3).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of EH domain-containing protein 3 (EHD3).	[13]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of EH domain-containing protein 3 (EHD3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of EH domain-containing protein 3 (EHD3).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of EH domain-containing protein 3 (EHD3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of EH domain-containing protein 3 (EHD3).	[18]

1 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 EH domain-containing protein 3 (EHD3).	[15]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Discovery of epigenetically silenced genes in acute myeloid leukemias.Leukemia. 2007 May;21(5):1026-34. doi: 10.1038/sj.leu.2404611. Epub 2007 Mar 1.
• [3] Retrospective Analysis of Cancer-Associated Myositis Patients over the Past 3 Decades in a Hungarian Myositis Cohort.Pathol Oncol Res. 2020 Jul;26(3):1749-1755. doi: 10.1007/s12253-019-00756-4. Epub 2019 Oct 23.
• [4] Ehd3, a regulator of vesicular trafficking, is silenced in gliomas and functions as a tumor suppressor by controlling cell cycle arrest and apoptosis.Carcinogenesis. 2014 Apr;35(4):877-85. doi: 10.1093/carcin/bgt399. Epub 2013 Dec 4.
• [5] Differential regulation of EHD3 in human and mammalian heart failure.J Mol Cell Cardiol. 2012 May;52(5):1183-90. doi: 10.1016/j.yjmcc.2012.02.008. Epub 2012 Mar 3.
• [6] EHD4 and CDH23 are interacting partners in cochlear hair cells.J Biol Chem. 2009 Jul 24;284(30):20121-9. doi: 10.1074/jbc.M109.025668. Epub 2009 Jun 1.
• [7] The gender-specific association of EHD3 polymorphisms with major depressive disorder.Neurosci Lett. 2014 May 1;567:11-4. doi: 10.1016/j.neulet.2014.02.055. Epub 2014 Mar 6.
• [8] Subsequent Sexual Risks Among Men Who Have Sex with Men May Differ by Sex of First Partner and Age at Sexual Debut: A Cross-Sectional Study in Beijing, China.AIDS Behav. 2017 Oct;21(10):2913-2923. doi: 10.1007/s10461-017-1677-x.
• [9] Histopathologic signs for the inflammatory role of Chlamydia pneumoniae in the high-grade atherosclerotic coronary artery wall.Angiology. 2004 Sep-Oct;55(5):525-31. doi: 10.1177/000331970405500508.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.