Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4KJ8F6)

• DOT Name: Ski oncogene (SKI)
• Synonyms: Proto-oncogene c-Ski
• Gene Name: SKI
• Related Disease:
  Glioblastoma multiforme
  Neural tube defect
  Shprintzen-Goldberg syndrome
  Acute myelogenous leukaemia
  Adenoma
  Aortic aneurysm
  Attention deficit hyperactivity disorder
  Autosomal dominant polycystic kidney disease
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Esophageal adenocarcinoma
  Fragile X syndrome
  Glioma
  Lung adenocarcinoma
  Melanoma
  Myelodysplastic syndrome
  Myeloid leukaemia
  Pachyonychia congenita 3
  Pancreatic cancer
  Plasma cell myeloma
  Pulmonary fibrosis
  Squamous cell carcinoma
  Trichohepatoenteric syndrome
  Triple negative breast cancer
  West syndrome
  Adult glioblastoma
  Autoimmune disease
  Neoplasm
  Acute intermittent hepatic porphyria
  Classic Hodgkin lymphoma
  Intellectual disability
  Lymphoma
  Malignant soft tissue neoplasm
  Neurofibromatosis type 1
  Pancreatic ductal carcinoma
  Prostate cancer
  Prostate carcinoma
  Sarcoma
• UniProt ID: SKI_HUMAN
• PDB ID: 1MR1; 1SBX; 5XOD; 6ZVQ
• Pfam ID: PF08782 ; PF02437
• Sequence:
  MEAAAGGRGCFQPHPGLQKTLEQFHLSSMSSLGGPAAFSARWAQEAYKKESAKEAGAAAV
  PAPVPAATEPPPVLHLPAIQPPPPVLPGPFFMPSDRSTERCETVLEGETISCFVVGGEKR
  LCLPQILNSVLRDFSLQQINAVCDELHIYCSRCTADQLEILKVMGILPFSAPSCGLITKT
  DAERLCNALLYGGAYPPPCKKELAASLALGLELSERSVRVYHECFGKCKGLLVPELYSSP
  SAACIQCLDCRLMYPPHKFVVHSHKALENRTCHWGFDSANWRAYILLSQDYTGKEEQARL
  GRCLDDVKEKFDYGNKYKRRVPRVSSEPPASIRPKTDDTSSQSPAPSEKDKPSSWLRTLA
  GSSNKSLGCVHPRQRLSAFRPWSPAVSASEKELSPHLPALIRDSFYSYKSFETAVAPNVA
  LAPPAQQKVVSSPPCAAAVSRAPEPLATCTQPRKRKLTVDTPGAPETLAPVAAPEEDKDS
  EAEVEVESREEFTSSLSSLSSPSFTSSSSAKDLGSPGARALPSAVPDAAAPADAPSGLEA
  ELEHLRQALEGGLDTKEAKEKFLHEVVKMRVKQEEKLSAALQAKRSLHQELEFLRVAKKE
  KLREATEAKRNLRKEIERLRAENEKKMKEANESRLRLKRELEQARQARVCDKGCEAGRLR
  AKYSAQIEDLQVKLQHAEADREQLRADLLREREAREHLEKVVKELQEQLWPRARPEAAGS
  EGAAELEP
• Function: May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway:
  Downregulation of SMAD2/3 (R-HSA-2173795)
  Signaling by BMP (R-HSA-201451)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Neural tube defect	DIS5J95E	Definitive	Biomarker	[2]
Shprintzen-Goldberg syndrome	DISQH6P3	Definitive	Autosomal dominant	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Adenoma	DIS78ZEV	Strong	Altered Expression	[5]
Aortic aneurysm	DISQ5KRA	Strong	Biomarker	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[7]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[8]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[5]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[12]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Altered Expression	[15]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[16]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[17]
Pachyonychia congenita 3	DISZLC6C	Strong	Genetic Variation	[18]
Pancreatic cancer	DISJC981	Strong	Biomarker	[19]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[20]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[21]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[22]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[23]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[24]
West syndrome	DISLIAU9	Strong	Biomarker	[25]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[26]
Autoimmune disease	DISORMTM	moderate	Biomarker	[27]
Neoplasm	DISZKGEW	moderate	Biomarker	[18]
Acute intermittent hepatic porphyria	DIS80J7E	Limited	Altered Expression	[28]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Biomarker	[29]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[30]
Lymphoma	DISN6V4S	Limited	Biomarker	[29]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[31]
Neurofibromatosis type 1	DIS53JH9	Limited	Genetic Variation	[32]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[28]
Prostate cancer	DISF190Y	Limited	Altered Expression	[33]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[33]
Sarcoma	DISZDG3U	Limited	Biomarker	[31]

5 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 Ski oncogene (SKI).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ski oncogene (SKI).	[40]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ski oncogene (SKI).	[48]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ski oncogene (SKI).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ski oncogene (SKI).	[52]

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 Ski oncogene (SKI).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ski oncogene (SKI).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ski oncogene (SKI).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ski oncogene (SKI).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ski oncogene (SKI).	[39]
Marinol	DM70IK5	Approved	Marinol increases the expression of Ski oncogene (SKI).	[41]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ski oncogene (SKI).	[42]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Ski oncogene (SKI).	[43]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Ski oncogene (SKI).	[44]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ski oncogene (SKI).	[45]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ski oncogene (SKI).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ski oncogene (SKI).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ski oncogene (SKI).	[47]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ski oncogene (SKI).	[49]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Ski oncogene (SKI).	[51]

References

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• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1.Nucleic Acids Res. 2018 Apr 20;46(7):3412-3428. doi: 10.1093/nar/gky119.
• [5] TGF-beta repressors SnoN and Ski are implicated in human colorectal carcinogenesis.Cell Oncol. 2009;31(1):41-51. doi: 10.3233/clo-2009-0460.
• [6] Mutations in the TGF- repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012 Nov;44(11):1249-54. doi: 10.1038/ng.2421. Epub 2012 Sep 30.
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• [8] c-Src inactivation reduces renal epithelial cell-matrix adhesion, proliferation, and cyst formation.Am J Physiol Cell Physiol. 2011 Aug;301(2):C522-9. doi: 10.1152/ajpcell.00163.2010. Epub 2011 Apr 20.
• [9] Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus.Hum Pathol. 2008 Mar;39(3):403-9. doi: 10.1016/j.humpath.2007.07.009.
• [10] A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.Elife. 2019 Oct 28;8:e47110. doi: 10.7554/eLife.47110.
• [11] SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Res. 2006 Feb 15;66(4):2279-86. doi: 10.1158/0008-5472.CAN-05-2057.
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• [17] The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.Haematologica. 2014 Apr;99(4):647-55. doi: 10.3324/haematol.2013.093971. Epub 2014 Jan 10.
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• [21] Abrogation of transforming growth factor--induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib).PLoS One. 2018 May 2;13(5):e0196559. doi: 10.1371/journal.pone.0196559. eCollection 2018.
• [22] Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma.Int J Cancer. 2004 Mar 1;108(6):818-24. doi: 10.1002/ijc.11651.
• [23] Combined Immunodeficiency in Patients With Trichohepatoenteric Syndrome.Front Immunol. 2018 May 11;9:1036. doi: 10.3389/fimmu.2018.01036. eCollection 2018.
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• [26] P144, a Transforming Growth Factor beta inhibitor peptide, generates antitumoral effects and modifies SMAD7 and SKI levels in human glioblastoma cell lines.Cancer Lett. 2016 Oct 10;381(1):67-75. doi: 10.1016/j.canlet.2016.07.029. Epub 2016 Jul 26.
• [27] SKI and SMAD4 are essential for IL-21-induced Th17 differentiation.Mol Immunol. 2019 Oct;114:260-268. doi: 10.1016/j.molimm.2019.07.029. Epub 2019 Aug 6.
• [28] Promoter hypomethylation of SKI in autoimmune pancreatitis.Pathol Res Pract. 2018 Apr;214(4):492-497. doi: 10.1016/j.prp.2018.03.005. Epub 2018 Mar 6.
• [29] The cellular homologue of the transforming gene of SKV avian retrovirus maps to human chromosome region 1q22----q24.Cytogenet Cell Genet. 1986;43(3-4):181-6. doi: 10.1159/000132318.
• [30] A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability.Am J Med Genet A. 2019 Jun;179(6):936-939. doi: 10.1002/ajmg.a.61088. Epub 2019 Mar 18.
• [31] Next generation sequencing analysis of miRNAs: MiR-127-3p inhibits glioblastoma proliferation and activates TGF- signaling by targeting SKI.OMICS. 2014 Mar;18(3):196-206. doi: 10.1089/omi.2013.0122. Epub 2014 Feb 11.
• [32] Differences in MWCNT- and SWCNT-induced DNA methylation alterations in association with the nuclear deposition.Part Fibre Toxicol. 2018 Feb 9;15(1):11. doi: 10.1186/s12989-018-0244-6.
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