Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWCCVF6)

• DOT Name: Dickkopf-related protein 4 (DKK4)
• Synonyms: Dickkopf-4; Dkk-4; hDkk-4
• Gene Name: DKK4
• Related Disease:
  Neoplasm
  Adenocarcinoma
  Adenoma
  Adrenocortical carcinoma, hereditary
  Bipolar disorder
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Depression
  Epithelial ovarian cancer
  Esophagitis
  Gastric cancer
  Gastroesophageal reflux disease
  Gastrointestinal stromal tumour
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Renal cell carcinoma
  Schizophrenia
  Stomach cancer
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Non-insulin dependent diabetes
  Type-1 diabetes
• UniProt ID: DKK4_HUMAN
• PDB ID: 5O57
• Pfam ID: PF04706 ; PF21481 ; PF21479
• Sequence:
  MVAAVLLGLSWLCSPLGALVLDFNNIRSSADLHGARKGSQCLSDTDCNTRKFCLQPRDEK
  PFCATCRGLRRRCQRDAMCCPGTLCVNDVCTTMEDATPILERQLDEQDGTHAEGTTGHPV
  QENQPKRKPSIKKSQGRKGQEGESCLRTFDCGPGLCCARHFWTKICKPVLLEGQVCSRRG
  HKDTAQAPEIFQRCDCGPGLLCRSQLTSNRQHARLRVCQKIEKL
• Function: Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease.
• Tissue Specificity: Expressed in cerebellum, T-cells, esophagus and lung.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Negative regulation of TCF-dependent signaling by WNT ligand antagonists (R-HSA-3772470)
  Signaling by LRP5 mutants (R-HSA-5339717)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Adrenocortical carcinoma, hereditary	DIS4PDHI	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[7]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Esophagitis	DISHVC9B	Strong	Altered Expression	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[9]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[2]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Pancreatic cancer	DISJC981	Strong	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[17]
Liver cancer	DISDE4BI	Limited	Biomarker	[17]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[18]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[18]

8 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 Dickkopf-related protein 4 (DKK4).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dickkopf-related protein 4 (DKK4).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dickkopf-related protein 4 (DKK4).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dickkopf-related protein 4 (DKK4).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Dickkopf-related protein 4 (DKK4).	[23]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Dickkopf-related protein 4 (DKK4).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dickkopf-related protein 4 (DKK4).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Dickkopf-related protein 4 (DKK4).	[27]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the secretion of Dickkopf-related protein 4 (DKK4).	[22]

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 increases the methylation of Dickkopf-related protein 4 (DKK4).	[26]

References

• [1] Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor.Cancer Med. 2019 Sep;8(11):5352-5366. doi: 10.1002/cam4.2437. Epub 2019 Jul 29.
• [2] Genetic Variants in the Wingless Antagonist Genes (sFRP, DKK, and Axin2) Predict the Overall Survival and Prognosis of North Indian Lung Cancer Patients Treated with Platinum-Based Doublet Chemotherapy.Cancer Biother Radiopharm. 2018 Dec;33(10):466-477. doi: 10.1089/cbr.2018.2491. Epub 2018 Oct 20.
• [3] DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer.Cancer Sci. 2009 Oct;100(10):1923-30. doi: 10.1111/j.1349-7006.2009.01272.x. Epub 2009 Jul 2.
• [4] Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.Mol Psychiatry. 2009 Jun;14(6):563-89. doi: 10.1038/mp.2009.2. Epub 2009 Feb 10.
• [5] High expression of the secreted protein dickkopf homolog 4: roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene.Int J Mol Med. 2014 May;33(5):1319-26. doi: 10.3892/ijmm.2014.1673. Epub 2014 Feb 25.
• [6] Dickkopf-4 is frequently down-regulated and inhibits growth of colorectal cancer cells.Cancer Lett. 2009 Apr 18;276(2):152-9. doi: 10.1016/j.canlet.2008.11.003. Epub 2008 Dec 6.
• [7] Genetic variants in the WNT signaling pathway are protectively associated with colorectal cancer in a Saudi population.Saudi J Biol Sci. 2019 Feb;26(2):286-293. doi: 10.1016/j.sjbs.2018.05.018. Epub 2018 May 17.
• [8] Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion.BMC Cancer. 2017 Jun 30;17(1):455. doi: 10.1186/s12885-017-3407-1.
• [9] Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett's patients and healthy controls.Am J Gastroenterol. 2006 Jul;101(7):1437-48. doi: 10.1111/j.1572-0241.2006.00584.x.
• [10] Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer.Oncogene. 2006 Apr 20;25(17):2546-57. doi: 10.1038/sj.onc.1209279.
• [11] Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4.Sci Rep. 2016 Jun 8;6:27558. doi: 10.1038/srep27558.
• [12] DKK4-knockdown enhances chemosensitivity of A549/DTX cells to docetaxel.Acta Biochim Biophys Sin (Shanghai). 2017 Oct 1;49(10):899-906. doi: 10.1093/abbs/gmx086.
• [13] Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.Nat Biotechnol. 2015 Jun;33(6):656-60. doi: 10.1038/nbt.3239. Epub 2015 May 25.
• [14] Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA-Seq.Tumour Biol. 2016 Aug;37(8):10827-38. doi: 10.1007/s13277-015-4379-x. Epub 2016 Feb 15.
• [15] Wnt antagonist gene polymorphisms and renal cancer.Cancer. 2009 Oct 1;115(19):4488-503. doi: 10.1002/cncr.24491.
• [16] Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4.Biol Psychiatry. 2008 Jan 1;63(1):13-6. doi: 10.1016/j.biopsych.2007.03.014. Epub 2007 Jun 5.
• [17] Plasma glutamate carboxypeptidase is a negative regulator in liver cancer metastasis.Oncotarget. 2016 Nov 29;7(48):79774-79786. doi: 10.18632/oncotarget.12967.
• [18] The economic impact of insulin-related hypoglycemia in Denmark: an analysis using the Local Impact of Hypoglycemia Tool.J Med Econ. 2017 Apr;20(4):363-370. doi: 10.1080/13696998.2016.1269774. Epub 2016 Dec 21.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [23] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [24] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.