Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT7SUVW)

• DOT Name: DNA-binding protein SATB1 (SATB1)
• Synonyms: Special AT-rich sequence-binding protein 1
• Gene Name: SATB1
• Related Disease:
  Developmental delay with dysmorphic facies and dental anomalies
  Syndromic intellectual disability
• UniProt ID: SATB1_HUMAN
• PDB ID: 1YSE; 2L1P; 2MW8; 2O49; 2O4A; 3NZL; 3TUO; 6LFF
• Pfam ID: PF02376 ; PF16557 ; PF00046 ; PF16534
• Sequence:
  MDHLNEATQGKEHSEMSNNVSDPKGPPAKIARLEQNGSPLGRGRLGSTGAKMQGVPLKHS
  GHLMKTNLRKGTMLPVFCVVEHYENAIEYDCKEEHAEFVLVRKDMLFNQLIEMALLSLGY
  SHSSAAQAKGLIQVGKWNPVPLSYVTDAPDATVADMLQDVYHVVTLKIQLHSCPKLEDLP
  PEQWSHTTVRNALKDLLKDMNQSSLAKECPLSQSMISSIVNSTYYANVSAAKCQEFGRWY
  KHFKKTKDMMVEMDSLSELSQQGANHVNFGQQPVPGNTAEQPPSPAQLSHGSQPSVRTPL
  PNLHPGLVSTPISPQLVNQQLVMAQLLNQQYAVNRLLAQQSLNQQYLNHPPPVSRSMNKP
  LEQQVSTNTEVSSEIYQWVRDELKRAGISQAVFARVAFNRTQGLLSEILRKEEDPKTASQ
  SLLVNLRAMQNFLQLPEAERDRIYQDERERSLNAASAMGPAPLISTPPSRPPQVKTATIA
  TERNGKPENNTMNINASIYDEIQQEMKRAKVSQALFAKVAATKSQGWLCELLRWKEDPSP
  ENRTLWENLSMIRRFLSLPQPERDAIYEQESNAVHHHGDRPPHIIHVPAEQIQQQQQQQQ
  QQQQQQQAPPPPQPQQQPQTGPRLPPRQPTVASPAESDEENRQKTRPRTKISVEALGILQ
  SFIQDVGLYPDEEAIQTLSAQLDLPKYTIIKFFQNQRYYLKHHGKLKDNSGLEVDVAEYK
  EEELLKDLEESVQDKNTNTLFSVKLEEELSVEGNTDINTDLKD
• Function: Crucial silencing factor contributing to the initiation of X inactivation mediated by Xist RNA that occurs during embryogenesis and in lymphoma. Binds to DNA at special AT-rich sequences, the consensus SATB1-binding sequence (CSBS), at nuclear matrix- or scaffold-associated regions. Thought to recognize the sugar-phosphate structure of double-stranded DNA. Transcriptional repressor controlling nuclear and viral gene expression in a phosphorylated and acetylated status-dependent manner, by binding to matrix attachment regions (MARs) of DNA and inducing a local chromatin-loop remodeling. Acts as a docking site for several chromatin remodeling enzymes (e.g. PML at the MHC-I locus) and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters and enhancers. Modulates genes that are essential in the maturation of the immune T-cell CD8SP from thymocytes. Required for the switching of fetal globin species, and beta- and gamma-globin genes regulation during erythroid differentiation. Plays a role in chromatin organization and nuclear architecture during apoptosis. Interacts with the unique region (UR) of cytomegalovirus (CMV). Alu-like motifs and SATB1-binding sites provide a unique chromatin context which seems preferentially targeted by the HIV-1 integration machinery. Moreover, HIV-1 Tat may overcome SATB1-mediated repression of IL2 and IL2RA (interleukin) in T-cells by binding to the same domain than HDAC1. Delineates specific epigenetic modifications at target gene loci, directly up-regulating metastasis-associated genes while down-regulating tumor-suppressor genes. Reprograms chromatin organization and the transcription profiles of breast tumors to promote growth and metastasis. Promotes neuronal differentiation of neural stem/progenitor cells in the adult subventricular zone, possibly by positively regulating the expression of NEUROD1.
• Tissue Specificity: Expressed predominantly in thymus.
• Reactome Pathway:
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental delay with dysmorphic facies and dental anomalies	DISACS2P	Strong	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	DNA-binding protein SATB1 (SATB1) decreases the response to substance of Arsenic trioxide.	[23]
Topotecan	DMP6G8T	Approved	DNA-binding protein SATB1 (SATB1) affects the response to substance of Topotecan.	[24]

20 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 DNA-binding protein SATB1 (SATB1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-binding protein SATB1 (SATB1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of DNA-binding protein SATB1 (SATB1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-binding protein SATB1 (SATB1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-binding protein SATB1 (SATB1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA-binding protein SATB1 (SATB1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA-binding protein SATB1 (SATB1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of DNA-binding protein SATB1 (SATB1).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of DNA-binding protein SATB1 (SATB1).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of DNA-binding protein SATB1 (SATB1).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of DNA-binding protein SATB1 (SATB1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of DNA-binding protein SATB1 (SATB1).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DNA-binding protein SATB1 (SATB1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA-binding protein SATB1 (SATB1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DNA-binding protein SATB1 (SATB1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-binding protein SATB1 (SATB1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA-binding protein SATB1 (SATB1).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of DNA-binding protein SATB1 (SATB1).	[20]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of DNA-binding protein SATB1 (SATB1).	[21]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA-binding protein SATB1 (SATB1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of DNA-binding protein SATB1 (SATB1).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the methylation of DNA-binding protein SATB1 (SATB1).	[19]

References

• [1] Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. Am J Hum Genet. 2021 Feb 4;108(2):346-356. doi: 10.1016/j.ajhg.2021.01.007. Epub 2021 Jan 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [10] 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.
• [11] 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.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] 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.
• [15] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [16] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [22] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [23] Silencing SATB1 inhibits the malignant phenotype and increases sensitivity of human osteosarcoma U2OS cells to arsenic trioxide. Int J Med Sci. 2014 Oct 2;11(12):1262-9. doi: 10.7150/ijms.10038. eCollection 2014.
• [24] 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.