Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZL05QN)

• DOT Name: Centromere protein W (CENPW)
• Synonyms: CENP-W; Cancer-up-regulated gene 2 protein
• Gene Name: CENPW
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: CENPW_HUMAN
• PDB ID: 7QOO; 7R5S; 7XHN; 7XHO; 7YWX
• Pfam ID: PF15510
• Sequence:
  MALSTIVSQRKQIKRKAPRGFLKRVFKRKKPQLRLEKSGDLLVHLNCLLFVHRLAEESRT
  NACASKCRVINKEHVLAAAKVILKKSRG
• Function: Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Part of a nucleosome-associated complex that binds specifically to histone H3-containing nucleosomes at the centromere, as opposed to nucleosomes containing CENPA. Component of the heterotetrameric CENP-T-W-S-X complex that binds and supercoils DNA, and plays an important role in kinetochore assembly. CENPW has a fundamental role in kinetochore assembly and function. It is one of the inner kinetochore proteins, with most further proteins binding downstream. Required for normal chromosome organization and normal progress through mitosis.
• Tissue Specificity: Highly expressed in ovary, liver, lung and pancreas and to a lower extent in breast and gastrointestinal tract cancers; such as those of the colon, rectum and stomach. Overexpressed in high grade breast invasive tumors. Expressed in many cancer cell types.
• Reactome Pathway: Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Centromere protein W (CENPW).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Centromere protein W (CENPW).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein W (CENPW).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centromere protein W (CENPW).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Centromere protein W (CENPW).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Centromere protein W (CENPW).	[9]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Centromere protein W (CENPW).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein W (CENPW).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Centromere protein W (CENPW).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein W (CENPW).	[11]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Centromere protein W (CENPW).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Centromere protein W (CENPW).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein W (CENPW).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein W (CENPW).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Centromere protein W (CENPW).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein W (CENPW).	[18]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Cancer upregulated gene (CUG)2 elevates YAP1 expression, leading to enhancement of epithelial-mesenchymal transition in human lung cancer cells.Biochem Biophys Res Commun. 2019 Mar 26;511(1):122-128. doi: 10.1016/j.bbrc.2019.02.036. Epub 2019 Feb 14.
• [3] CGK062, a small chemical molecule, inhibits cancer upregulated gene 2induced oncogenesis through NEK2 and catenin.Int J Oncol. 2019 Apr;54(4):1295-1305. doi: 10.3892/ijo.2019.4724. Epub 2019 Feb 22.
• [4] 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.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.