Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1TFJK0)

• DOT Name: Protein cornichon homolog 4 (CNIH4)
• Synonyms: CNIH-4; Cornichon family AMPA receptor auxiliary protein 4
• Gene Name: CNIH4
• Related Disease:
  Type-1/2 diabetes
  Colon cancer
  Colon carcinoma
• UniProt ID: CNIH4_HUMAN
• Pfam ID: PF03311
• Sequence:
  MEAVVFVFSLLDCCALIFLSVYFIITLSDLECDYINARSCCSKLNKWVIPELIGHTIVTV
  LLLMSLHWFIFLLNLPVATWNIYRYIMVPSGNMGVFDPTEIHNRGQLKSHMKEAMIKLGF
  HLLCFFMYLYSMILALIND
• Function: Involved in G protein-coupled receptors (GPCRs) trafficking from the endoplasmic reticulum to the cell surface; it promotes the exit of GPCRs from the early secretory pathway, likely through interaction with the COPII machinery.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[1]
Colon cancer	DISVC52G	Limited	Biomarker	[2]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[2]

16 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 Protein cornichon homolog 4 (CNIH4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein cornichon homolog 4 (CNIH4).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein cornichon homolog 4 (CNIH4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein cornichon homolog 4 (CNIH4).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein cornichon homolog 4 (CNIH4).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein cornichon homolog 4 (CNIH4).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein cornichon homolog 4 (CNIH4).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein cornichon homolog 4 (CNIH4).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein cornichon homolog 4 (CNIH4).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Protein cornichon homolog 4 (CNIH4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein cornichon homolog 4 (CNIH4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein cornichon homolog 4 (CNIH4).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein cornichon homolog 4 (CNIH4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein cornichon homolog 4 (CNIH4).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein cornichon homolog 4 (CNIH4).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Protein cornichon homolog 4 (CNIH4).	[19]

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 affects the methylation of Protein cornichon homolog 4 (CNIH4).	[13]

References

• [1] Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.Ann Rheum Dis. 2016 Apr;75(4):652-9. doi: 10.1136/annrheumdis-2014-206191. Epub 2015 Feb 2.
• [2] The protein secretion modulator TMED9 drives CNIH4/TGF/GLI signaling opposing TMED3-WNT-TCF to promote colon cancer metastases.Oncogene. 2019 Jul;38(29):5817-5837. doi: 10.1038/s41388-019-0845-z. Epub 2019 Jun 28.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.