Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6X1Q7)

• DOT Name: Cohesin subunit SA-2 (STAG2)
• Synonyms: SCC3 homolog 2; Stromal antigen 2
• Gene Name: STAG2
• Related Disease:
  Adenocarcinoma
  Bone osteosarcoma
  Ewing sarcoma
  Holoprosencephaly
  leukaemia
  Oral cancer
  Osteosarcoma
  Bladder cancer
  Breast carcinoma
  Carcinoma
  Colorectal carcinoma
  Deafness
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Intellectual disability
  Isolated congenital microcephaly
  Lung cancer
  Melanoma
  Mullegama-Klein-Martinez syndrome
  Myelodysplastic syndrome
  Myeloid leukaemia
  Neoplasm
  Polydactyly
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Adult glioblastoma
  Cornelia de Lange syndrome
  Leukemia
  Advanced cancer
  Glioblastoma multiforme
  Neuroblastoma
  Transitional cell carcinoma
  X-linked lymphoproliferative syndrome
• UniProt ID: STAG2_HUMAN
• PDB ID: 4PJU; 4PJW; 4PK7; 6QNX; 7ZJS
• Pfam ID: PF21581 ; PF08514
• Sequence:
  MIAAPEIPTDFNLLQESETHFSSDTDFEDIEGKNQKQGKGKTCKKGKKGPAEKGKGGNGG
  GKPPSGPNRMNGHHQQNGVENMMLFEVVKMGKSAMQSVVDDWIESYKHDRDIALLDLINF
  FIQCSGCKGVVTAEMFRHMQNSEIIRKMTEEFDEDSGDYPLTMAGPQWKKFKSSFCEFIG
  VLVRQCQYSIIYDEYMMDTVISLLTGLSDSQVRAFRHTSTLAAMKLMTALVNVALNLSIN
  MDNTQRQYEAERNKMIGKRANERLELLLQKRKELQENQDEIENMMNAIFKGVFVHRYRDA
  IAEIRAICIEEIGIWMKMYSDAFLNDSYLKYVGWTMHDKQGEVRLKCLTALQGLYYNKEL
  NSKLELFTSRFKDRIVSMTLDKEYDVAVQAIKLLTLVLQSSEEVLTAEDCENVYHLVYSA
  HRPVAVAAGEFLYKKLFSRRDPEEDGMMKRRGRQGPNANLVKTLVFFFLESELHEHAAYL
  VDSMWDCATELLKDWECMNSLLLEEPLSGEEALTDRQESALIEIMLCTIRQAAECHPPVG
  RGTGKRVLTAKEKKTQLDDRTKITELFAVALPQLLAKYSVDAEKVTNLLQLPQYFDLEIY
  TTGRLEKHLDALLRQIRNIVEKHTDTDVLEACSKTYHALCNEEFTIFNRVDISRSQLIDE
  LADKFNRLLEDFLQEGEEPDEDDAYQVLSTLKRITAFHNAHDLSKWDLFACNYKLLKTGI
  ENGDMPEQIVIHALQCTHYVILWQLAKITESSSTKEDLLRLKKQMRVFCQICQHYLTNVN
  TTVKEQAFTILCDILMIFSHQIMSGGRDMLEPLVYTPDSSLQSELLSFILDHVFIEQDDD
  NNSADGQQEDEASKIEALHKRRNLLAAFCKLIVYTVVEMNTAADIFKQYMKYYNDYGDII
  KETMSKTRQIDKIQCAKTLILSLQQLFNEMIQENGYNFDRSSSTFSGIKELARRFALTFG
  LDQLKTREAIAMLHKDGIEFAFKEPNPQGESHPPLNLAFLDILSEFSSKLLRQDKRTVYV
  YLEKFMTFQMSLRREDVWLPLMSYRNSLLAGGDDDTMSVISGISSRGSTVRSKKSKPSTG
  KRKVVEGMQLSLTEESSSSDSMWLSREQTLHTPVMMQTPQLTSTIMREPKRLRPEDSFMS
  VYPMQTEHHQTPLDYNRRGTSLMEDDEEPIVEDVMMSSEGRIEDLNEGMDFDTMDIDLPP
  SKNRRERTELKPDFFDPASIMDESVLGVSMF
• Function: Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Establishment of Sister Chromatid Cohesion (R-HSA-2468052)
  Cohesin Loading onto Chromatin (R-HSA-2470946)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[2]
Ewing sarcoma	DISQYLV3	Definitive	Genetic Variation	[3]
Holoprosencephaly	DISR35EC	Definitive	Altered Expression	[4]
leukaemia	DISS7D1V	Definitive	Genetic Variation	[2]
Oral cancer	DISLD42D	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Deafness	DISKCLH4	Strong	Biomarker	[8]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Genetic Variation	[9]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Mullegama-Klein-Martinez syndrome	DISAG1SZ	Strong	X-linked	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[12]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[15]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Urothelial carcinoma	DISRTNTN	Strong	Genetic Variation	[16]
Adult glioblastoma	DISVP4LU	moderate	Genetic Variation	[17]
Cornelia de Lange syndrome	DISEQSXO	moderate	Genetic Variation	[18]
Leukemia	DISNAKFL	moderate	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[19]
Glioblastoma multiforme	DISK8246	Limited	Genetic Variation	[17]
Neuroblastoma	DISVZBI4	Limited	Genetic Variation	[20]
Transitional cell carcinoma	DISWVVDR	Limited	Genetic Variation	[16]
X-linked lymphoproliferative syndrome	DISA7MJ4	Limited	CausalMutation	[21]

11 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 Cohesin subunit SA-2 (STAG2).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cohesin subunit SA-2 (STAG2).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cohesin subunit SA-2 (STAG2).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cohesin subunit SA-2 (STAG2).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cohesin subunit SA-2 (STAG2).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cohesin subunit SA-2 (STAG2).	[27]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cohesin subunit SA-2 (STAG2).	[28]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cohesin subunit SA-2 (STAG2).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cohesin subunit SA-2 (STAG2).	[28]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Cohesin subunit SA-2 (STAG2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cohesin subunit SA-2 (STAG2).	[33]

3 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 Cohesin subunit SA-2 (STAG2).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cohesin subunit SA-2 (STAG2).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Cohesin subunit SA-2 (STAG2).	[31]

References

• [1] STAG2 expression in oral cancer and potentially malignant lesions.Tumour Biol. 2014 Apr;35(4):3641-5. doi: 10.1007/s13277-013-1482-8. Epub 2013 Dec 8.
• [2] STAG2 loss-of-function mutation induces PD-L1 expression in U2OS cells.Ann Transl Med. 2019 Apr;7(7):127. doi: 10.21037/atm.2019.02.23.
• [3] Cohesin mutations in myeloid malignancies made simple.Curr Opin Hematol. 2018 Mar;25(2):61-66. doi: 10.1097/MOH.0000000000000405.
• [4] Cohesin complex-associated holoprosencephaly.Brain. 2019 Sep 1;142(9):2631-2643. doi: 10.1093/brain/awz210.
• [5] The role of STAG2 in bladder cancer.Pharmacol Res. 2018 May;131:143-149. doi: 10.1016/j.phrs.2018.02.025. Epub 2018 Mar 1.
• [6] Mutational and expressional analyses of STAG2 gene in solid cancers.Neoplasma. 2012;59(5):524-9. doi: 10.4149/neo_2012_067.
• [7] STAG2 loss of expression is rare in aneuploid malignant salivary gland neoplasms.J Oral Pathol Med. 2014 Apr;43(4):273-5. doi: 10.1111/jop.12127.
• [8] Microduplication of chromosome Xq25 encompassing STAG2 gene in a boy with intellectual disability.Eur J Med Genet. 2015 Feb;58(2):116-21. doi: 10.1016/j.ejmg.2014.10.002. Epub 2014 Oct 24.
• [9] The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.PLoS Genet. 2014 Jul 10;10(7):e1004475. doi: 10.1371/journal.pgen.1004475. eCollection 2014 Jul.
• [10] Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.Nat Med. 2016 Sep;22(9):1056-61. doi: 10.1038/nm.4155. Epub 2016 Aug 8.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] Dynamics of clonal evolution in myelodysplastic syndromes.Nat Genet. 2017 Feb;49(2):204-212. doi: 10.1038/ng.3742. Epub 2016 Dec 19.
• [13] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms.Nat Genet. 2013 Oct;45(10):1232-7. doi: 10.1038/ng.2731. Epub 2013 Aug 18.
• [14] Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.Cell Stem Cell. 2019 Nov 7;25(5):682-696.e8. doi: 10.1016/j.stem.2019.08.003. Epub 2019 Sep 5.
• [15] Mutations in STAG2 cause an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphia: Expanding the phenotype in males.Mol Genet Genomic Med. 2019 Feb;7(2):e00501. doi: 10.1002/mgg3.501. Epub 2018 Nov 16.
• [16] The evolving genomic landscape of urothelial carcinoma.Nat Rev Urol. 2017 Feb 7;14(4):215-229. doi: 10.1038/nrurol.2017.11. Online ahead of print.
• [17] Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition.Mol Cancer Ther. 2014 Mar;13(3):724-32. doi: 10.1158/1535-7163.MCT-13-0749. Epub 2013 Dec 19.
• [18] Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.Genet Med. 2019 Mar;21(3):663-675. doi: 10.1038/s41436-018-0085-6. Epub 2018 Aug 30.
• [19] A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers.Nat Commun. 2019 Apr 11;10(1):1686. doi: 10.1038/s41467-019-09659-z.
• [20] Aneuploidy in neuroblastoma tumors is not associated with inactivating point mutations in the STAG2 gene.BMC Med Genet. 2013 Oct 2;14:102. doi: 10.1186/1471-2350-14-102.
• [21] Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis.Ital J Pediatr. 2016 May 21;42(1):50. doi: 10.1186/s13052-016-0262-7.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [26] 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.
• [27] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [28] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [29] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [30] 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.
• [31] 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.
• [32] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [33] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.