Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDYJ12A)

• DOT Name: Spindle and kinetochore-associated protein 1 (SKA1)
• Gene Name: SKA1
• Related Disease:
  Advanced cancer
  Bladder cancer
  Bone osteosarcoma
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Stomach cancer
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  X-linked dominant hypophosphatemic rickets
  Adult glioblastoma
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Lentivirus infection
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Thyroid gland papillary carcinoma
• UniProt ID: SKA1_HUMAN
• PDB ID: 4AJ5; 4C9Y; 4CA0
• Pfam ID: PF07160
• Sequence:
  MASSDLEQLCSHVNEKIGNIKKTLSLRNCGQEPTLKTVLNKIGDEIIVINELLNKLELEI
  QYQEQTNNSLKELCESLEEDYKDIEHLKENVPSHLPQVTVTQSCVKGSDLDPEEPIKVEE
  PEPVKKPPKEQRSIKEMPFITCDEFNGVPSYMKSRLTYNQINDVIKEINKAVISKYKILH
  QPKKSMNSVTRNLYHRFIDEETKDTKGRYFIVEADIKEFTTLKADKKFHVLLNILRHCRR
  LSEVRGGGLTRYVIT
• Function: Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint. The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies. The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner. Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules. In the complex, it mediates the interaction with microtubules.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[7]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
X-linked dominant hypophosphatemic rickets	DISU3OP6	Strong	Biomarker	[11]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[12]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[13]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[12]
Lentivirus infection	DISX17PY	moderate	Altered Expression	[12]
Aplasia cutis congenita	DISMDAYM	Limited	Biomarker	[14]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[15]

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 Spindle and kinetochore-associated protein 1 (SKA1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[20]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[23]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[27]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[28]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Spindle and kinetochore-associated protein 1 (SKA1).	[30]

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 Spindle and kinetochore-associated protein 1 (SKA1).	[21]

References

• [1] SKA1 overexpression is associated with theprognosis of esophageal squamous cell carcinoma and regulates cell proliferation and migration.Int J Mol Med. 2019 Nov;44(5):1971-1978. doi: 10.3892/ijmm.2019.4343. Epub 2019 Sep 17.
• [2] High expression of spindle and kinetochore- associated protein 1 predicts early recurrence and progression of non-muscle invasive bladder cancer.Cancer Biomark. 2018;22(3):543-549. doi: 10.3233/CBM-181202.
• [3] SKA1 induces denovo MTX-resistance in osteosarcoma through inhibiting FPGS transcription.FEBS J. 2019 Jun;286(12):2399-2414. doi: 10.1111/febs.14808. Epub 2019 Apr 2.
• [4] Spindle and kinetochore-associated protein 1 is overexpressed in gastric cancer and modulates cell growth.Mol Cell Biochem. 2014 Jun;391(1-2):167-74. doi: 10.1007/s11010-014-1999-1. Epub 2014 Mar 14.
• [5] SKA1 promotes malignant phenotype and progression of glioma via multiple signaling pathways.Cancer Cell Int. 2019 Dec 3;19:324. doi: 10.1186/s12935-019-1047-z. eCollection 2019.
• [6] LINC00339 promotes growth and invasiveness of hepatocellular carcinoma by the miR-1182/SKA1 pathway.Onco Targets Ther. 2019 Jun 6;12:4481-4488. doi: 10.2147/OTT.S207397. eCollection 2019.
• [7] Risk stratification of triple-negative breast cancer with core gene signatures associated with chemoresponse and prognosis.Breast Cancer Res Treat. 2019 Nov;178(1):185-197. doi: 10.1007/s10549-019-05366-x. Epub 2019 Jul 24.
• [8] PPAR promotes diabetes-associated centrosome amplification via increasing the expression of SKA1 directly at the transcriptional level.J Cell Physiol. 2019 Nov;234(11):20694-20703. doi: 10.1002/jcp.28674. Epub 2019 Apr 15.
• [9] Overexpression of spindle and kinetochore-associated protein 1 contributes to the progression of prostate cancer.Tumour Biol. 2017 Jun;39(6):1010428317701918. doi: 10.1177/1010428317701918.
• [10] Regulation of spindle and kinetochore-associated protein 1 by antitumor miR-10a-5p in renal cell carcinoma.Cancer Sci. 2017 Oct;108(10):2088-2101. doi: 10.1111/cas.13331. Epub 2017 Aug 19.
• [11] Overexpression of human PHEX under the human beta-actin promoter does not fully rescue the Hyp mouse phenotype.J Bone Miner Res. 2005 Jul;20(7):1149-60. doi: 10.1359/JBMR.050212. Epub 2005 Feb 21.
• [12] Lentivirus-mediated silencing of spindle and kinetochore-associated protein 1 inhibits the proliferation and invasion of neuronal glioblastoma cells.Mol Med Rep. 2015 May;11(5):3533-8. doi: 10.3892/mmr.2015.3175. Epub 2015 Jan 9.
• [13] Long non-coding RNA ZFAS1 promotes proliferation and metastasis of clear cell renal cell carcinoma via targeting miR-10a/SKA1 pathway.Biomed Pharmacother. 2019 Mar;111:917-925. doi: 10.1016/j.biopha.2018.12.143. Epub 2019 Jan 7.
• [14] Knockdown of SKA1 gene inhibits cell proliferation and metastasis in human adenoid cystic carcinoma.Biomed Pharmacother. 2017 Jun;90:8-14. doi: 10.1016/j.biopha.2017.03.029. Epub 2017 Mar 21.
• [15] Expression of Spindle and Kinetochore-Associated Protein 1 Is Associated with Poor Prognosis in Papillary Thyroid Carcinoma.Dis Markers. 2015;2015:616541. doi: 10.1155/2015/616541. Epub 2015 May 4.
• [16] 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.
• [17] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [24] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [29] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [30] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.