Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVYF4XT)

• DOT Name: Spindle and kinetochore-associated protein 2 (SKA2)
• Synonyms: Protein FAM33A
• Gene Name: SKA2
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Glioma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Breast neoplasm
  Small-cell lung cancer
  Sickle-cell anaemia
• UniProt ID: SKA2_HUMAN
• PDB ID: 4AJ5
• Pfam ID: PF16740
• Sequence:
  MEAEVDKLELMFQKAESDLDYIQYRLEYEIKTNHPDSASEKNPVTLLKELSVIKSRYQTL
  YARFKPVAVEQKESKSRICATVKKTMNMIQKLQKQTDLELSPLTKEEKTAAEQFKFHMPD
  L
• 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. In the complex, it is required for SKA1 localization. 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.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	moderate	Biomarker	[5]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[5]
Sickle-cell anaemia	DIS5YNZB	Limited	Altered Expression	[6]

2 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 Spindle and kinetochore-associated protein 2 (SKA2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Spindle and kinetochore-associated protein 2 (SKA2).	[18]

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 Spindle and kinetochore-associated protein 2 (SKA2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[16]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Spindle and kinetochore-associated protein 2 (SKA2).	[24]

References

• [1] SKA2 mediates invasion and metastasis in human breast cancer via EMT.Mol Med Rep. 2019 Jan;19(1):515-523. doi: 10.3892/mmr.2018.9623. Epub 2018 Nov 2.
• [2] PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer.BMB Rep. 2019 Feb;52(2):157-162. doi: 10.5483/BMBRep.2019.52.2.207.
• [3] Epigenetic modification of miR-141 regulates SKA2 by an endogenous 'sponge' HOTAIR in glioma.Oncotarget. 2016 May 24;7(21):30610-25. doi: 10.18632/oncotarget.8895.
• [4] GLUCOCORTICOID RECEPTOR-RELATED GENES: GENOTYPE AND BRAIN GENE EXPRESSION RELATIONSHIPS TO SUICIDE AND MAJOR DEPRESSIVE DISORDER.Depress Anxiety. 2016 Jun;33(6):531-540. doi: 10.1002/da.22499. Epub 2016 Mar 31.
• [5] Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor.J Endocrinol. 2008 Sep;198(3):499-509. doi: 10.1677/JOE-08-0019. Epub 2008 Jun 26.
• [6] Peroxisome proliferator-activated receptor--mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease.Biosci Rep. 2015 Oct 12;35(6):e00275. doi: 10.1042/BSR20150190.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] 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.
• [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] 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.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [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] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] 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.