Details of Drug Off-Target (DOT)

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

• DOT Name: Spindle and kinetochore-associated protein 3 (SKA3)
• Gene Name: SKA3
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Medulloblastoma
  Breast cancer
  Breast carcinoma
  Neoplasm
  Colorectal adenoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SKA3_HUMAN
• PDB ID: 4AJ5
• Sequence:
  MDPIRSFCGKLRSLASTLDCETARLQRALDGEESDFEDYPMRILYDLHSEVQTLKDDVNI
  LLDKARLENQEGIDFIKATKVLMEKNSMDIMKIREYFQKYGYSPRVKKNSVHEQEAINSD
  PELSNCENFQKTDVKDDLSDPPVASSCISEKSPRSPQLSDFGLERYIVSQVLPNPPQAVN
  NYKEEPVIVTPPTKQSLVKVLKTPKCALKMDDFECVTPKLEHFGISEYTMCLNEDYTMGL
  KNARNNKSEEAIDTESRLNDNVFATPSPIIQQLEKSDAEYTNSPLVPTFCTPGLKIPSTK
  NSIALVSTNYPLSKTNSSSNDLEVEDRTSLVLNSDTCFENLTDPSSPTISSYENLLRTPT
  PPEVTKIPEDILQLLSKYNSNLATPIAIKAVPPSKRFLKHGQNIRDVSNKEN
• Function: Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. 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. In the complex, it mediates the microtubule-stimulated oligomerization. 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.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Biomarker	[4]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Colorectal adenoma	DISTSVHM	Limited	Altered Expression	[5]
Prostate cancer	DISF190Y	Limited	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[6]

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 Spindle and kinetochore-associated protein 3 (SKA3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[15]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[12]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[16]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Spindle and kinetochore-associated protein 3 (SKA3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Spindle and kinetochore-associated protein 3 (SKA3).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Spindle and kinetochore-associated protein 3 (SKA3).	[21]

References

• [1] SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway.Cancer Cell Int. 2018 Nov 14;18:183. doi: 10.1186/s12935-018-0670-4. eCollection 2018.
• [2] SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma.Cell Death Dis. 2019 Dec 5;10(12):929. doi: 10.1038/s41419-019-2163-3.
• [3] Dysregulated circular RNAs in medulloblastoma regulate proliferation and growth of tumor cells via host genes.Cancer Med. 2018 Dec;7(12):6147-6157. doi: 10.1002/cam4.1613. Epub 2018 Nov 6.
• [4] Identification of hub genes to regulate breast cancer metastasis to brain by bioinformatics analyses.J Cell Biochem. 2019 Jun;120(6):9522-9531. doi: 10.1002/jcb.28228. Epub 2018 Dec 3.
• [5] 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.
• [6] GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes.Clin Exp Metastasis. 2015 Dec;32(8):769-82. doi: 10.1007/s10585-015-9745-y. Epub 2015 Oct 1.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] 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.
• [17] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] 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.
• [22] 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.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.