Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0HJ277)

• DOT Name: Glucose-induced degradation protein 8 homolog (GID8)
• Synonyms: Two hybrid-associated protein 1 with RanBPM; Twa1
• Gene Name: GID8
• Related Disease:
  Stomach cancer
  Colorectal carcinoma
  Gastric cancer
  Neoplasm
• UniProt ID: GID8_HUMAN
• PDB ID: 7NSC
• Pfam ID: PF10607 ; PF08513
• Sequence:
  MSYAEKPDEITKDEWMEKLNNLHVQRADMNRLIMNYLVTEGFKEAAEKFRMESGIEPSVD
  LETLDERIKIREMILKGQIQEAIALINSLHPELLDTNRYLYFHLQQQHLIELIRQRETEA
  ALEFAQTQLAEQGEESRECLTEMERTLALLAFDSPEESPFGDLLHTMQRQKVWSEVNQAV
  LDYENRESTPKLAKLLKLLLWAQNELDQKKVKYPKMTDLSKGVIEEPK
• Function: Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1. Acts as a positive regulator of Wnt signaling pathway by promoting beta-catenin (CTNNB1) nuclear accumulation.
• Tissue Specificity: Up-regulated in colorectal cancer tissues (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Glucose-induced degradation protein 8 homolog (GID8).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucose-induced degradation protein 8 homolog (GID8).	[4]

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 increases the methylation of Glucose-induced degradation protein 8 homolog (GID8).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Glucose-induced degradation protein 8 homolog (GID8).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Glucose-induced degradation protein 8 homolog (GID8).	[7]

References

• [1] Overexpression of TWA1 predicts poor prognosis in patients with gastric cancer.Pathol Res Pract. 2019 Nov;215(11):152594. doi: 10.1016/j.prp.2019.152594. Epub 2019 Aug 16.
• [2] Twa1/Gid8 is a -catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis.Cell Res. 2017 Dec;27(12):1422-1440. doi: 10.1038/cr.2017.107. Epub 2017 Aug 22.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.