Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHROI0H)

• DOT Name: Kinetochore-associated protein DSN1 homolog (DSN1)
• Gene Name: DSN1
• Related Disease:
  Advanced cancer
  Colorectal adenoma
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: DSN1_HUMAN
• PDB ID: 5LSI; 5LSJ; 5LSK
• Pfam ID: PF08202
• Sequence:
  MTSVTRSEIIDEKGPVMSKTHDHQLESSLSPVEVFAKTSASLEMNQGVSEERIHLGSSPK
  KGGNCDLSHQERLQSKSLHLSPQEQSASYQDRRQSWRRASMKETNRRKSLHPIHQGITEL
  SRSISVDLAESKRLGCLLLSSFQFSIQKLEPFLRDTKGFSLESFRAKASSLSEELKHFAD
  GLETDGTLQKCFEDSNGKASDFSLEASVAEMKEYITKFSLERQTWDQLLLHYQQEAKEIL
  SRGSTEAKITEVKVEPMTYLGSSQNEVLNTKPDYQKILQNQSKVFDCMELVMDELQGSVK
  QLQAFMDESTQCFQKVSVQLGKRSMQQLDPSPARKLLKLQLQNPPAIHGSGSGSCQ
• Function: Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Neutrophil degranulation (R-HSA-6798695)
  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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[1]
Colorectal adenoma	DISTSVHM	Limited	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[10]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Kinetochore-associated protein DSN1 homolog (DSN1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinetochore-associated protein DSN1 homolog (DSN1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Kinetochore-associated protein DSN1 homolog (DSN1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Kinetochore-associated protein DSN1 homolog (DSN1).	[20]

References

• [1] Elevated DSN1 expression is associated with poor survival in patients with hepatocellular carcinoma.Hum Pathol. 2018 Nov;81:113-120. doi: 10.1016/j.humpath.2018.06.032. Epub 2018 Jul 3.
• [2] Over-expression of AURKA, SKA3 and DSN1 contributes to colorectal adenoma to carcinoma progression.Oncotarget. 2016 Jul 19;7(29):45803-45818. doi: 10.18632/oncotarget.9960.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.