Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3MO97)

• DOT Name: Protein naked cuticle homolog 1 (NKD1)
• Synonyms: Naked-1; hNkd; hNkd1
• Gene Name: NKD1
• Related Disease:
  Acute myelogenous leukaemia
  Adenoma
  Advanced cancer
  Bone osteosarcoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Pancreatic cancer
  Ankylosing spondylitis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Breast carcinoma
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Juvenile idiopathic arthritis
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Adult glioblastoma
  Breast cancer
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colorectal carcinoma
  Colorectal neoplasm
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Invasive ductal breast carcinoma
  Liver cancer
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: NKD1_HUMAN
• Sequence:
  MGKLHSKPAAVCKRRESPEGDSFAVSAAWARKGIEEWIGRQRCPGGVSGPRQLRLAGTIG
  RSTRELVGDVLRDTLSEEEEDDFRLEVALPPEKTDGLGSGDEKKMERVSEPCPGSKKQLK
  FEELQCDVSMEEDSRQEWTFTLYDFDNNGKVTREDITSLLHTIYEVVDSSVNHSPTSSKM
  LRVKLTVAPDGSQSKRSVLVNQADLQSARPRAETKPTEDLRSWEKKQRAPLRFQGDSRLE
  QSGCYHHCVDENIERRNHYLDLAGIENYTSQFGPGSPSVAQKSELPPRTSNPTRSRSHEP
  EAIHIPHRKPQGVDPASFHFLDTPIAKVSELQQRLRGTQDGSKHFVRSPKAQGKSVGVGH
  VARGARNKPPLGPAIPAVSPSAHLAASPALLPSLAPLGHKKHKHRAKESQQGCRGLQAPL
  ASGGPVLGREHLRELPALVVYESQAGQPVQRHEHHHHHEHHHHYHHFYQT
• Function: Cell autonomous antagonist of the canonical Wnt signaling pathway. May activate a second Wnt signaling pathway that controls planar cell polarity.
• Tissue Specificity: Expressed in colon, heart, kidney, leukocyte, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine and spleen.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[7]
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[8]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[8]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[8]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[9]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[8]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[8]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[8]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[8]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[8]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[8]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[8]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[8]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[9]
Carcinoma	DISH9F1N	Limited	Biomarker	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Colorectal neoplasm	DISR1UCN	Limited	Genetic Variation	[12]
Epithelial ovarian cancer	DIS56MH2	Limited	Posttranslational Modification	[13]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[10]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[9]
Liver cancer	DISDE4BI	Limited	Altered Expression	[11]
Ovarian cancer	DISZJHAP	Limited	Posttranslational Modification	[13]
Ovarian neoplasm	DISEAFTY	Limited	Posttranslational Modification	[13]

4 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 Protein naked cuticle homolog 1 (NKD1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein naked cuticle homolog 1 (NKD1).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein naked cuticle homolog 1 (NKD1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein naked cuticle homolog 1 (NKD1).	[27]

14 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 Protein naked cuticle homolog 1 (NKD1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein naked cuticle homolog 1 (NKD1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein naked cuticle homolog 1 (NKD1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Protein naked cuticle homolog 1 (NKD1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein naked cuticle homolog 1 (NKD1).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein naked cuticle homolog 1 (NKD1).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein naked cuticle homolog 1 (NKD1).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein naked cuticle homolog 1 (NKD1).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein naked cuticle homolog 1 (NKD1).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Protein naked cuticle homolog 1 (NKD1).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein naked cuticle homolog 1 (NKD1).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein naked cuticle homolog 1 (NKD1).	[22]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein naked cuticle homolog 1 (NKD1).	[28]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Protein naked cuticle homolog 1 (NKD1).	[29]

References

• [1] Low NKD1 expression predicts adverse prognosis in cytogenetically normal acute myeloid leukemia.Tumour Biol. 2017 Apr;39(4):1010428317699123. doi: 10.1177/1010428317699123.
• [2] Reorganisation of Wnt-response pathways in colorectal tumorigenesis.Br J Cancer. 2008 Apr 22;98(8):1437-42. doi: 10.1038/sj.bjc.6604327. Epub 2008 Apr 15.
• [3] NKD1 correlates with a poor prognosis and inhibits cell proliferation by inducing p53 expression in hepatocellular carcinoma.Tumour Biol. 2016 Oct;37(10):14059-14067. doi: 10.1007/s13277-016-5173-0. Epub 2016 Aug 9.
• [4] Downregulation of NKD1 in human osteosarcoma and its clinical significance.Mol Med Rep. 2018 Jan;17(1):1111-1117. doi: 10.3892/mmr.2017.7968. Epub 2017 Nov 6.
• [5] Long non-coding RNA HNF1A-AS1 promotes hepatocellular carcinoma cell proliferation by repressing NKD1 and P21 expression.Biomed Pharmacother. 2017 May;89:926-932. doi: 10.1016/j.biopha.2017.01.031. Epub 2017 Mar 8.
• [6] Down-regulation of NKD1 increases the invasive potential of non-small-cell lung cancer and correlates with a poor prognosis.BMC Cancer. 2011 May 20;11:186. doi: 10.1186/1471-2407-11-186.
• [7] Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2.Int J Oncol. 2001 Nov;19(5):963-9.
• [8] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [9] NKD1 down-regulation is associated with poor prognosis in breast invasive ductal carcinoma.Int J Clin Exp Pathol. 2015 Apr 1;8(4):4015-21. eCollection 2015.
• [10] The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter.Oncotarget. 2018 Feb 14;9(21):15512-15525. doi: 10.18632/oncotarget.24496. eCollection 2018 Mar 20.
• [11] NKD1 marks intestinal and liver tumors linked to aberrant Wnt signaling.Cell Signal. 2015 Feb;27(2):245-56. doi: 10.1016/j.cellsig.2014.11.008. Epub 2014 Nov 14.
• [12] Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/beta-catenin signaling.PLoS One. 2009 Nov 24;4(11):e7982. doi: 10.1371/journal.pone.0007982.
• [13] Systematic CpG islands methylation profiling of genes in the wnt pathway in epithelial ovarian cancer identifies biomarkers of progression-free survival.Clin Cancer Res. 2011 Jun 15;17(12):4052-62. doi: 10.1158/1078-0432.CCR-10-3021. Epub 2011 Apr 1.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [19] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] 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.
• [23] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] 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.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [29] Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril. 2014 May;101(5):1441-9. doi: 10.1016/j.fertnstert.2014.01.017. Epub 2014 Feb 15.