Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQWI68Q)

• DOT Name: Sal-like protein 2 (SALL2)
• Synonyms: Zinc finger protein 795; Zinc finger protein SALL2; Zinc finger protein Spalt-2; Sal-2; hSal2
• Gene Name: SALL2
• Related Disease:
  Neural tube defect
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Immunodeficiency
  Neoplasm
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Sarcoma
  Synovial sarcoma
  Coloboma
  T-cell acute lymphoblastic leukaemia
  Coloboma of optic nerve
  Childhood kidney Wilms tumor
  Coloboma, ocular, autosomal recessive
  Wilms tumor
• UniProt ID: SALL2_HUMAN
• Pfam ID: PF00096 ; PF13912
• Sequence:
  MSRRKQRKPQQLISDCEGPSASENGDASEEDHPQVCAKCCAQFTDPTEFLAHQNACSTDP
  PVMVIIGGQENPNNSSASSEPRPEGHNNPQVMDTEHSNPPDSGSSVPTDPTWGPERRGEE
  SSGHFLVAATGTAAGGGGGLILASPKLGATPLPPESTPAPPPPPPPPPPPGVGSGHLNIP
  LILEELRVLQQRQIHQMQMTEQICRQVLLLGSLGQTVGAPASPSELPGTGTASSTKPLLP
  LFSPIKPVQTSKTLASSSSSSSSSSGAETPKQAFFHLYHPLGSQHPFSAGGVGRSHKPTP
  APSPALPGSTDQLIASPHLAFPSTTGLLAAQCLGAARGLEATASPGLLKPKNGSGELSYG
  EVMGPLEKPGGRHKCRFCAKVFGSDSALQIHLRSHTGERPYKCNVCGNRFTTRGNLKVHF
  HRHREKYPHVQMNPHPVPEHLDYVITSSGLPYGMSVPPEKAEEEAATPGGGVERKPLVAS
  TTALSATESLTLLSTSAGTATAPGLPAFNKFVLMKAVEPKNKADENTPPGSEGSAISGVA
  ESSTATRMQLSKLVTSLPSWALLTNHFKSTGSFPFPYVLEPLGASPSETSKLQQLVEKID
  RQGAVAVTSAASGAPTTSAPAPSSSASSGPNQCVICLRVLSCPRALRLHYGQHGGERPFK
  CKVCGRAFSTRGNLRAHFVGHKASPAARAQNSCPICQKKFTNAVTLQQHVRMHLGGQIPN
  GGTALPEGGGAAQENGSEQSTVSGARSFPQQQSQQPSPEEELSEEEEEEDEEEEEDVTDE
  DSLAGRGSESGGEKAISVRGDSEEASGAEEEVGTVAAAATAGKEMDSNEKTTQQSSLPPP
  PPPDSLDQPQPMEQGSSGVLGGKEEGGKPERSSSPASALTPEGEATSVTLVEELSLQEAM
  RKEPGESSSRKACEVCGQAFPSQAALEEHQKTHPKEGPLFTCVFCRQGFLERATLKKHML
  LAHHQVQPFAPHGPQNIAALSLVPGCSPSITSTGLSPFPRKDDPTIP
• Function: Probable transcription factor that plays a role in eye development before, during, and after optic fissure closure.
• Tissue Specificity: Highest levels in adult brain (in different areas). Lower levels in heart; very low levels in kidney and pancreas. Expressed throughout the retina and lens vesicle as well as the periocular mesenchyme.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neural tube defect	DIS5J95E	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Biomarker	[7]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[1]
Coloboma	DISP39N5	moderate	Biomarker	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	moderate	FusionGene	[8]
Coloboma of optic nerve	DISR9DCH	Disputed	GermlineCausalMutation	[9]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Altered Expression	[10]
Coloboma, ocular, autosomal recessive	DISEH1QX	Limited	Autosomal recessive	[9]
Wilms tumor	DISB6T16	Limited	Altered Expression	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Sal-like protein 2 (SALL2) affects the response to substance of Mitoxantrone.	[26]

13 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 Sal-like protein 2 (SALL2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sal-like protein 2 (SALL2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sal-like protein 2 (SALL2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sal-like protein 2 (SALL2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sal-like protein 2 (SALL2).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sal-like protein 2 (SALL2).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of Sal-like protein 2 (SALL2).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Sal-like protein 2 (SALL2).	[18]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Sal-like protein 2 (SALL2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sal-like protein 2 (SALL2).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sal-like protein 2 (SALL2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sal-like protein 2 (SALL2).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sal-like protein 2 (SALL2).	[25]

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 Sal-like protein 2 (SALL2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sal-like protein 2 (SALL2).	[23]

References

• [1] Developmental SALL2 transcription factor: a new player in cancer.Carcinogenesis. 2017 Jul 1;38(7):680-690. doi: 10.1093/carcin/bgx036.
• [2] SALL2 represses cyclins D1 and E1 expression and restrains G1/S cell cycle transition and cancer-related phenotypes.Mol Oncol. 2018 Jun;12(7):1026-1046. doi: 10.1002/1878-0261.12308. Epub 2018 May 21.
• [3] Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer.EMBO Mol Med. 2019 Dec;11(12):e10638. doi: 10.15252/emmm.201910638. Epub 2019 Oct 28.
• [4] mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes.J Cancer. 2017 Feb 25;8(4):646-656. doi: 10.7150/jca.15652. eCollection 2017.
• [5] Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.Cell. 2014 Apr 24;157(3):580-94. doi: 10.1016/j.cell.2014.02.030. Epub 2014 Apr 10.
• [6] Promoter methylation of the SALL2 tumor suppressor gene in ovarian cancers.Mol Oncol. 2013 Jun;7(3):419-27. doi: 10.1016/j.molonc.2012.11.005. Epub 2012 Dec 12.
• [7] Tissue microarray validation of epidermal growth factor receptor and SALL2 in synovial sarcoma with comparison to tumors of similar histology.Am J Pathol. 2003 Oct;163(4):1449-56. doi: 10.1016/S0002-9440(10)63502-X.
• [8] Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia.Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):373-378. doi: 10.1073/pnas.1717125115. Epub 2017 Dec 26.
• [9] Mutation of SALL2 causes recessive ocular coloboma in humans and mice. Hum Mol Genet. 2014 May 15;23(10):2511-26. doi: 10.1093/hmg/ddt643. Epub 2014 Jan 9.
• [10] Cloning and characterization of two promoters for the human HSAL2 gene and their transcriptional repression by the Wilms tumor suppressor gene product.J Biol Chem. 2001 Dec 21;276(51):48223-30. doi: 10.1074/jbc.M106468200. Epub 2001 Sep 27.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] 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.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] 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.
• [25] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.