Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCYT3I6)

• DOT Name: Protein naked cuticle homolog 2 (NKD2)
• Synonyms: Naked-2; hNkd2
• Gene Name: NKD2
• Related Disease:
  Carcinoma of esophagus
  Colorectal carcinoma
  Esophageal cancer
  Gastric cancer
  Glioblastoma multiforme
  Malignant peripheral nerve sheath tumor
  Neoplasm
  Neoplasm of esophagus
  Sarcoma
  Soft tissue sarcoma
  Stomach cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Osteosarcoma
• UniProt ID: NKD2_HUMAN
• Sequence:
  MGKLQSKHAAAARKRRESPEGDSFVASAYASGRKGAEEAERRARDKQELPNGDPKEGPFR
  EDQCPLQVALPAEKAEGREHPGQLLSADDGERAANREGPRGPGGQRLNIDALQCDVSVEE
  DDRQEWTFTLYDFDNCGKVTREDMSSLMHTIYEVVDASVNHSSGSSKTLRVKLTVSPEPS
  SKRKEGPPAGQDREPTRCRMEGELAEEPRVADRRLSAHVRRPSTDPQPCSERGPYCVDEN
  TERRNHYLDLAGIENYTSRFGPGSPPVQAKQEPQGRASHLQARSRSQEPDTHAVHHRRSQ
  VLVEHVVPASEPAARALDTQPRPKGPEKQFLKSPKGSGKPPGVPASSKSGKAFSYYLPAV
  LPPQAPQDGHHLPQPPPPPYGHKRYRQKGREGHSPLKAPHAQPATVEHEVVRDLPPTPAG
  EGYAVPVIQRHEHHHHHEHHHHHHHHHFHPS
• Function: Cell autonomous antagonist of the canonical Wnt signaling pathway. May activate a second Wnt signaling pathway that controls planar cell polarity. Required for processing of TGFA and for targeting of TGFA to the basolateral membrane of polarized epithelial cells.
• Tissue Specificity: Expressed in kidney, lung, pancreas and spleen.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of esophagus	DISS6G4D	Strong	Posttranslational Modification	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Esophageal cancer	DISGB2VN	Strong	Posttranslational Modification	[1]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neoplasm of esophagus	DISOLKAQ	Strong	Posttranslational Modification	[1]
Sarcoma	DISZDG3U	Strong	Biomarker	[4]
Soft tissue sarcoma	DISSN8XB	Strong	Altered Expression	[4]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[6]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[7]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[5]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Protein naked cuticle homolog 2 (NKD2) affects the response to substance of Temozolomide.	[27]
DTI-015	DMXZRW0	Approved	Protein naked cuticle homolog 2 (NKD2) affects the response to substance of DTI-015.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein naked cuticle homolog 2 (NKD2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein naked cuticle homolog 2 (NKD2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein naked cuticle homolog 2 (NKD2).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein naked cuticle homolog 2 (NKD2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein naked cuticle homolog 2 (NKD2).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein naked cuticle homolog 2 (NKD2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein naked cuticle homolog 2 (NKD2).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein naked cuticle homolog 2 (NKD2).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein naked cuticle homolog 2 (NKD2).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein naked cuticle homolog 2 (NKD2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein naked cuticle homolog 2 (NKD2).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein naked cuticle homolog 2 (NKD2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein naked cuticle homolog 2 (NKD2).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein naked cuticle homolog 2 (NKD2).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein naked cuticle homolog 2 (NKD2).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein naked cuticle homolog 2 (NKD2).	[25]
Isoarnebin 4	DM0B7NO	Investigative	Isoarnebin 4 decreases the expression of Protein naked cuticle homolog 2 (NKD2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein naked cuticle homolog 2 (NKD2).	[15]

References

• [1] Silencing NKD2 by Promoter Region Hypermethylation Promotes Esophageal Cancer Progression by Activating Wnt Signaling.J Thorac Oncol. 2016 Nov;11(11):1912-1926. doi: 10.1016/j.jtho.2016.06.015. Epub 2016 Jun 30.
• [2] Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction.Am J Hum Genet. 2019 Jul 3;105(1):29-47. doi: 10.1016/j.ajhg.2019.05.004. Epub 2019 Jun 13.
• [3] Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas.Int J Cancer. 2010 Jun 1;126(11):2584-93. doi: 10.1002/ijc.24981.
• [4] Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas.Genes Chromosomes Cancer. 2006 Sep;45(9):829-38. doi: 10.1002/gcc.20343.
• [5] Low expression of NKD2 is associated with enhanced cell proliferation and poor prognosis in human hepatocellular carcinoma.Hum Pathol. 2018 Feb;72:80-90. doi: 10.1016/j.humpath.2017.09.016. Epub 2017 Nov 8.
• [6] Silencing NKD2 by promoter region hypermethylation promotes gastric cancer invasion and metastasis by up-regulating SOX18 in human gastric cancer.Oncotarget. 2015 Oct 20;6(32):33470-85. doi: 10.18632/oncotarget.5272.
• [7] miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells. Biochem Biophys Res Commun. 2016 Mar 18;471(4):479-85.
• [8] Epigenetic silencing of NKD2, a major component of Wnt signaling, promotes breast cancer growth.Oncotarget. 2015 Sep 8;6(26):22126-38. doi: 10.18632/oncotarget.4244.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [18] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] 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.
• [26] Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation. Chem Biol Interact. 2023 Sep 1;382:110588. doi: 10.1016/j.cbi.2023.110588. Epub 2023 Jun 1.
• [27] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.