Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ4UL5S)

• DOT Name: Kelch domain-containing protein 4 (KLHDC4)
• Gene Name: KLHDC4
• Related Disease:
  Nasopharyngeal carcinoma
  Neoplasm
• UniProt ID: KLDC4_HUMAN
• Pfam ID: PF13415 ; PF13418
• Sequence:
  MGKKGKKEKKGRGAEKTAAKMEKKVSKRSRKEEEDLEALIAHFQTLDAKRTQTVELPCPP
  PSPRLNASLSVHPEKDELILFGGEYFNGQKTFLYNELYVYNTRKDTWTKVDIPSPPPRRC
  AHQAVVVPQGGGQLWVFGGEFASPNGEQFYHYKDLWVLHLATKTWEQVKSTGGPSGRSGH
  RMVAWKRQLILFGGFHESTRDYIYYNDVYAFNLDTFTWSKLSPSGTGPTPRSGCQMSVTP
  QGGIVVYGGYSKQRVKKDVDKGTRHSDMFLLKPEDGREDKWVWTRMNPSGVKPTPRSGFS
  VAMAPNHQTLFFGGVCDEEEEESLSGEFFNDLYFYDATRNRWFEGQLKGPKSEKKKRRRG
  RKEEPEGGSRPACGGAGTQGPVQLVKEVVAEDGTVVTIKQVLTAPGSAGQPRSEDEDSLE
  EAGSPAPGPCPRSNAMLAVKHGVLYVYGGMFEAGDRQVTLSDLHCLDLHRMEAWKALVEM
  DPETQEWLEETDSEEDSEEVEGAEGGVDDEDSGEESGAED

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[1]
Neoplasm	DISZKGEW	Limited	Biomarker	[1]

6 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 Kelch domain-containing protein 4 (KLHDC4).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kelch domain-containing protein 4 (KLHDC4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kelch domain-containing protein 4 (KLHDC4).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Kelch domain-containing protein 4 (KLHDC4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Kelch domain-containing protein 4 (KLHDC4).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Kelch domain-containing protein 4 (KLHDC4).	[10]

6 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 Kelch domain-containing protein 4 (KLHDC4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kelch domain-containing protein 4 (KLHDC4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kelch domain-containing protein 4 (KLHDC4).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Kelch domain-containing protein 4 (KLHDC4).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Kelch domain-containing protein 4 (KLHDC4).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kelch domain-containing protein 4 (KLHDC4).	[12]

References

• [1] Upregulation of KLHDC4 Predicts a Poor Prognosis in Human Nasopharyngeal Carcinoma.PLoS One. 2016 Mar 31;11(3):e0152820. doi: 10.1371/journal.pone.0152820. eCollection 2016.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [9] 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.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.