Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGZI072)

• DOT Name: Eukaryotic translation initiation factor 4H (EIF4H)
• Synonyms: eIF-4H; Williams-Beuren syndrome chromosomal region 1 protein
• Gene Name: EIF4H
• Related Disease:
  Advanced cancer
  Herpes simplex infection
  Lung adenocarcinoma
  Neoplasm
  Colorectal carcinoma
• UniProt ID: IF4H_HUMAN
• Pfam ID: PF00076
• Sequence:
  MADFDTYDDRAYSSFGGGRGSRGSAGGHGSRSQKELPTEPPYTAYVGNLPFNTVQGDIDA
  IFKDLSIRSVRLVRDKDTDKFKGFCYVEFDEVDSLKEALTYDGALLGDRSLRVDIAEGRK
  QDKGGFGFRKGGPDDRGMGSSRESRGGWDSRDDFNSGFRDDFLGGRGGSRPGDRRTGPPM
  GSRFRDGPPLRGSNMDFREPTEEERAQRPRLQLKPRTVATPLNQVANPNSAIFGGARPRE
  EVVQKEQE
• Function: Stimulates the RNA helicase activity of EIF4A in the translation initiation complex. Binds weakly mRNA.
• Tissue Specificity: The short isoform is the predominant isoform and is expressed alone in liver and skeletal muscle. Both isoforms are expressed in fibroblast, spleen, testis and bone marrow. Levels are high in lung and pancreas and low in heart, frontal cortex and kidney.
• Reactome Pathway:
  Translation initiation complex formation (R-HSA-72649)
  Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S (R-HSA-72662)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Disputed	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[9]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Eukaryotic translation initiation factor 4H (EIF4H).	[12]

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 Eukaryotic translation initiation factor 4H (EIF4H).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Eukaryotic translation initiation factor 4H (EIF4H).	[11]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paraquat	DMR8O3X	Investigative	Paraquat increases the degradation of Eukaryotic translation initiation factor 4H (EIF4H).	[13]
D-glucose	DMMG2TO	Investigative	D-glucose increases the degradation of Eukaryotic translation initiation factor 4H (EIF4H).	[13]

References

• [1] Key contribution of eIF4H-mediated translational control in tumor promotion.Oncotarget. 2015 Nov 24;6(37):39924-40. doi: 10.18632/oncotarget.5442.
• [2] A bimodal switch in global protein translation coupled to eIF4H relocalisation during advancing cell-cell transmission of herpes simplex virus.PLoS Pathog. 2018 Jul 20;14(7):e1007196. doi: 10.1371/journal.ppat.1007196. eCollection 2018 Jul.
• [3] Overexpression of miR-519d in lung adenocarcinoma inhibits cell proliferation and invasion via the association of eIF4H.Tumour Biol. 2017 Mar;39(3):1010428317694566. doi: 10.1177/1010428317694566.
• [4] An alternative splicing isoform of eukaryotic initiation factor 4H promotes tumorigenesis in vivo and is a potential therapeutic target for human cancer.Int J Cancer. 2011 Mar 1;128(5):1018-30. doi: 10.1002/ijc.25419.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [9] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [10] 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.
• [11] 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.
• [12] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [13] Targetome analysis of chaperone-mediated autophagy in cancer cells. Autophagy. 2019 Sep;15(9):1558-1571. doi: 10.1080/15548627.2019.1586255. Epub 2019 Mar 20.