Details of Drug Off-Target (DOT)

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

• DOT Name: KH homology domain-containing protein 4 (KHDC4)
• Synonyms: Brings lots of money 7; Pre-mRNA splicing factor protein KHDC4
• Gene Name: KHDC4
• Related Disease:
  Prostate cancer
  Prostate carcinoma
• UniProt ID: KHDC4_HUMAN
• PDB ID: 2YQR
• Sequence:
  MSAGSATHPGAGGRRSKWDQPAPAPLLFLPPAAPGGEVTSSGGSPGGTTAAPSGALDAAA
  AVAAKINAMLMAKGKLKPTQNASEKLQAPGKGLTSNKSKDDLVVAEVEINDVPLTCRNLL
  TRGQTQDEISRLSGAAVSTRGRFMTTEEKAKVGPGDRPLYLHVQGQTRELVDRAVNRIKE
  IITNGVVKAATGTSPTFNGATVTVYHQPAPIAQLSPAVSQKPPFQSGMHYVQDKLFVGLE
  HAVPTFNVKEKVEGPGCSYLQHIQIETGAKVFLRGKGSGCIEPASGREAFEPMYIYISHP
  KPEGLAAAKKLCENLLQTVHAEYSRFVNQINTAVPLPGYTQPSAISSVPPQPPYYPSNGY
  QSGYPVVPPPQQPVQPPYGVPSIVPPAVSLAPGVLPALPTGVPPVPTQYPITQVQPPAST
  GQSPMGGPFIPAAPVKTALPAGPQPQPQPQPPLPSQPQAQKRRFTEELPDERESGLLGYQ
  HGPIHMTNLGTGFSSQNEIEGAGSKPASSSGKERERDRQLMPPPAFPVTGIKTESDERNG
  SGTLTGSHDYPAKKMKTTEKGFGLVAYAADSSDEEEEHGGHKNASSFPQGWSLGYQYPSS
  QPRAKQQMPFWMAP
• Function: RNA-binding protein involved in pre-mRNA splicing. Interacts with the PRP19C/Prp19 complex/NTC/Nineteen complex which is part of the spliceosome. Involved in regulating splice site selection. Binds preferentially RNA with A/C rich sequences and poly-C stretches.
• Tissue Specificity: Ubiquitous. Expressed at high level in skeletal muscle, kidney, heart, brain and liver.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Strong	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of KH homology domain-containing protein 4 (KHDC4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of KH homology domain-containing protein 4 (KHDC4).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of KH homology domain-containing protein 4 (KHDC4).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of KH homology domain-containing protein 4 (KHDC4).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of KH homology domain-containing protein 4 (KHDC4).	[13]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of KH homology domain-containing protein 4 (KHDC4).	[14]

2 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 KH homology domain-containing protein 4 (KHDC4).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of KH homology domain-containing protein 4 (KHDC4).	[11]

References

• [1] SNORA42 enhances prostate cancer cell viability, migration and EMT and is correlated with prostate cancer poor prognosis.Int J Biochem Cell Biol. 2018 Sep;102:138-150. doi: 10.1016/j.biocel.2018.07.009. Epub 2018 Jul 24.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [13] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.