Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGCN3B5)

• DOT Name: CXXC-type zinc finger protein 5 (CXXC5)
• Synonyms: CF5; Putative MAPK-activating protein PM08; Putative NF-kappa-B-activating protein 102; Retinoid-inducible nuclear factor; RINF
• Gene Name: CXXC5
• UniProt ID: CXXC5_HUMAN
• PDB ID: 5W9S
• Pfam ID: PF02008
• Sequence:
  MSSLGGGSQDAGGSSSSSTNGSGGSGSSGPKAGAADKSAVVAAAAPASVADDTPPPERRN
  KSGIISEPLNKSLRRSRPLSHYSSFGSSGGSGGGSMMGGESADKATAAAAAASLLANGHD
  LAAAMAVDKSNPTSKHKSGAVASLLSKAERATELAAEGQLTLQQFAQSTEMLKRVVQEHL
  PLMSEAGAGLPDMEAVAGAEALNGQSDFPYLGAFPINPGLFIMTPAGVFLAESALHMAGL
  AEYPMQGELASAISSGKKKRKRCGMCAPCRRRINCEQCSSCRNRKTGHQICKFRKCEELK
  KKPSAALEKVMLPTGAAFRWFQ
• Function: May indirectly participate in activation of the NF-kappa-B and MAPK pathways. Acts as a mediator of BMP4-mediated modulation of canonical Wnt signaling activity in neural stem cells. Required for DNA damage-induced ATM phosphorylation, p53 activation and cell cycle arrest. Involved in myelopoiesis. Transcription factor. Binds to the oxygen responsive element of COX4I2 and represses its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen). May repress COX4I2 transactivation induced by CHCHD2 and RBPJ. Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG.
• Reactome Pathway: Estrogen-dependent gene expression (R-HSA-9018519)

Molecular Interaction Atlas (MIA) of This DOT

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of CXXC-type zinc finger protein 5 (CXXC5).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of CXXC-type zinc finger protein 5 (CXXC5).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CXXC-type zinc finger protein 5 (CXXC5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of CXXC-type zinc finger protein 5 (CXXC5).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CXXC-type zinc finger protein 5 (CXXC5).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CXXC-type zinc finger protein 5 (CXXC5).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of CXXC-type zinc finger protein 5 (CXXC5).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of CXXC-type zinc finger protein 5 (CXXC5).	[19]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [9] 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.
• [10] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.
• [19] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.