Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYK9KOX)

• DOT Name: Centromere protein M (CENPM)
• Synonyms: CENP-M; Interphase centromere complex protein 39; Proliferation-associated nuclear element protein 1
• Gene Name: CENPM
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Hepatitis B virus infection
  Liver cancer
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Leukemia
  Lymphoma
  Schizophrenia
• UniProt ID: CENPM_HUMAN
• PDB ID: 4P0T; 4WAU; 7PKN; 7QOO; 7R5S; 7R5V; 7XHN; 7XHO; 7YWX; 7YYH
• Pfam ID: PF11111
• Sequence:
  MSVLRPLDKLPGLNTATILLVGTEDALLQQLADSMLKEDCASELKVHLAKSLPLPSSVNR
  PRIDLIVFVVNLHSKYSLQNTEESLRHVDASFFLGKVCFLATGAGRESHCSIHRHTVVKL
  AHTYQSPLLYCDLEVEGFRATMAQRLVRVLQICAGHVPGVSALNLLSLLRSSEGPSLEDL
• 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.
• Tissue Specificity: Isoform 3 is highly expressed in spleen, and intermediately in heart, prostate and ovary. Isoform 3 is highly expressed in resting CD19 B-cells and B-lineage chronic lymphocytic leukemia (B-CLL) cells and weakly expressed in activated B-cells. Isoform 1 is selectively expressed in activated CD19 cells and weakly in resting CD19 B-cells.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Altered Expression	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Bladder cancer	DISUHNM0	moderate	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[3]
Leukemia	DISNAKFL	Limited	Biomarker	[4]
Lymphoma	DISN6V4S	Limited	Biomarker	[4]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[5]

2 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 Centromere protein M (CENPM).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Centromere protein M (CENPM).	[13]

17 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 M (CENPM).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Centromere protein M (CENPM).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Centromere protein M (CENPM).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Centromere protein M (CENPM).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Centromere protein M (CENPM).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Centromere protein M (CENPM).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centromere protein M (CENPM).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centromere protein M (CENPM).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Centromere protein M (CENPM).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Centromere protein M (CENPM).	[16]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Centromere protein M (CENPM).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Centromere protein M (CENPM).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Centromere protein M (CENPM).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Centromere protein M (CENPM).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Centromere protein M (CENPM).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Centromere protein M (CENPM).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Centromere protein M (CENPM).	[12]

References

• [1] Upregulation of CENPM promotes hepatocarcinogenesis through mutiple mechanisms.J Exp Clin Cancer Res. 2019 Nov 8;38(1):458. doi: 10.1186/s13046-019-1444-0.
• [2] A three-gene novel predictor for improving the prognosis of cervical cancer.Oncol Lett. 2019 Nov;18(5):4907-4915. doi: 10.3892/ol.2019.10815. Epub 2019 Sep 5.
• [3] Bioinformatics Analysis Identified Key Molecular Changes in Bladder Cancer Development and Recurrence.Biomed Res Int. 2019 Nov 16;2019:3917982. doi: 10.1155/2019/3917982. eCollection 2019.
• [4] The proliferation associated nuclear element (PANE1) is conserved between mammals and fish and preferentially expressed in activated lymphoid cells.Gene Expr Patterns. 2004 Jul;4(4):389-95. doi: 10.1016/j.modgep.2004.01.008.
• [5] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] 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.
• [21] 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.