Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61RBF5)

• DOT Name: Eukaryotic translation initiation factor 3 subunit H (EIF3H)
• Synonyms: eIF3h; Eukaryotic translation initiation factor 3 subunit 3; eIF-3-gamma; eIF3 p40 subunit
• Gene Name: EIF3H
• Related Disease:
  Non-small-cell lung cancer
  Advanced cancer
  Benign prostatic hyperplasia
  Breast neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Cutaneous mastocytosis
  Endometrial cancer
  Endometrial carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Carcinoma
  Gastric cancer
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Intellectual disability
  Prostate neoplasm
• UniProt ID: EIF3H_HUMAN
• PDB ID: 3J8B; 3J8C; 6YBD; 6ZMW; 6ZON; 6ZP4; 6ZVJ; 7A09; 7QP6; 7QP7; 8PPL
• Pfam ID: PF19445 ; PF01398
• Sequence:
  MASRKEGTGSTATSSSSTAGAAGKGKGKGGSGDSAVKQVQIDGLVVLKIIKHYQEEGQGT
  EVVQGVLLGLVVEDRLEITNCFPFPQHTEDDADFDEVQYQMEMMRSLRHVNIDHLHVGWY
  QSTYYGSFVTRALLDSQFSYQHAIEESVVLIYDPIKTAQGSLSLKAYRLTPKLMEVCKEK
  DFSPEALKKANITFEYMFEEVPIVIKNSHLINVLMWELEKKSAVADKHELLSLASSNHLG
  KNLQLLMDRVDEMSQDIVKYNTYMRNTSKQQQQKHQYQQRRQQENMQRQSRGEPPLPEED
  LSKLFKPPQPPARMDSLLIAGQINTYCQNIKEFTAQNLGKLFMAQALQEYNN
• Function: Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression.
• KEGG Pathway: Measles (hsa05162)
• Reactome Pathway:
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[6]
Cutaneous mastocytosis	DISLBZEF	Strong	Altered Expression	[7]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[9]
Carcinoma	DISH9F1N	moderate	Altered Expression	[3]
Gastric cancer	DISXGOUK	moderate	Biomarker	[10]
Stomach cancer	DISKIJSX	moderate	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[11]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[11]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[24]

3 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 affects the methylation of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Eukaryotic translation initiation factor 3 subunit H (EIF3H).	[22]

References

• [1] MYC and EIF3H Coamplification significantly improve response and survival of non-small cell lung cancer patients (NSCLC) treated with gefitinib.J Thorac Oncol. 2009 Apr;4(4):472-8. doi: 10.1097/JTO.0b013e31819a5767.
• [2] mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.Nature. 2018 Sep;561(7724):556-560. doi: 10.1038/s41586-018-0538-8. Epub 2018 Sep 19.
• [3] Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer.Br J Cancer. 2004 Mar 8;90(5):1041-6. doi: 10.1038/sj.bjc.6601648.
• [4] Amplification and overexpression of p40 subunit of eukaryotic translation initiation factor 3 in breast and prostate cancer.Am J Pathol. 1999 Jun;154(6):1777-83. doi: 10.1016/S0002-9440(10)65433-8.
• [5] Integrated Analysis of the Gene Expression Changes During Colorectal Cancer Progression by Bioinformatic Methods.J Comput Biol. 2019 Oct;26(10):1168-1176. doi: 10.1089/cmb.2019.0056. Epub 2019 Jun 26.
• [6] A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.Nat Genet. 2008 May;40(5):623-30. doi: 10.1038/ng.111. Epub 2008 Mar 30.
• [7] PTK2 and EIF3S3 genes may be amplification targets at 8q23-q24 and are associated with large hepatocellular carcinomas.Hepatology. 2003 Nov;38(5):1242-9. doi: 10.1053/jhep.2003.50457.
• [8] The Prognostic Significance of Eukaryotic Translation Initiation Factors (eIFs) in Endometrial Cancer.Int J Mol Sci. 2019 Dec 6;20(24):6169. doi: 10.3390/ijms20246169.
• [9] Amplification of EIF3S3 gene is associated with advanced stage in prostate cancer.Am J Pathol. 2001 Dec;159(6):2089-94. doi: 10.1016/S0002-9440(10)63060-X.
• [10] Eukaryotic translation initiation factor EIF3H potentiates gastric carcinoma cell proliferation.Tissue Cell. 2018 Aug;53:23-29. doi: 10.1016/j.tice.2018.05.006. Epub 2018 May 8.
• [11] Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.Hum Mol Genet. 2014 Nov 15;23(22):6034-46. doi: 10.1093/hmg/ddu300. Epub 2014 Jun 13.
• [12] Microcephaly-thin corpus callosum syndrome maps to 8q23.2-q24.12.Pediatr Neurol. 2012 Jun;46(6):363-8. doi: 10.1016/j.pediatrneurol.2012.03.014.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] 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.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.