Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYDQZ1T)

• DOT Name: Transcription factor Sp3 (SP3)
• Synonyms: SPR-2
• Gene Name: SP3
• Related Disease:
  Myocardial infarction
  Neoplasm
  Hepatocellular carcinoma
  Malignant soft tissue neoplasm
  Multiple sclerosis
  Plasma cell myeloma
  Rhabdomyosarcoma
  Sarcoma
  Urinary bladder neoplasm
  Chronic obstructive pulmonary disease
  Glioma
  Leiomyosarcoma
  Nephropathy
  Neuroblastoma
  Type-1 diabetes
• UniProt ID: SP3_HUMAN
• Pfam ID: PF00096
• Sequence:
  MTAPEKPVKQEEMAALDVDSGGGGGGGGGHGEYLQQQQQHGNGAVAAAAAAQDTQPSPLA
  LLAATCSKIGPPSPGDDEEEAAAAAGAPAAAGATGDLASAQLGGAPNRWEVLSATPTTIK
  DEAGNLVQIPSAATSSGQYVLPLQNLQNQQIFSVAPGSDSSNGTVSSVQYQVIPQIQSAD
  GQQVQIGFTGSSDNGGINQESSQIQIIPGSNQTLLASGTPSANIQNLIPQTGQVQVQGVA
  IGGSSFPGQTQVVANVPLGLPGNITFVPINSVDLDSLGLSGSSQTMTAGINADGHLINTG
  QAMDSSDNSERTGERVSPDINETNTDTDLFVPTSSSSQLPVTIDSTGILQQNTNSLTTSS
  GQVHSSDLQGNYIQSPVSEETQAQNIQVSTAQPVVQHLQLQESQQPTSQAQIVQGITPQT
  IHGVQASGQNISQQALQNLQLQLNPGTFLIQAQTVTPSGQVTWQTFQVQGVQNLQNLQIQ
  NTAAQQITLTPVQTLTLGQVAAGGAFTSTPVSLSTGQLPNLQTVTVNSIDSAGIQLHPGE
  NADSPADIRIKEEEPDPEEWQLSGDSTLNTNDLTHLRVQVVDEEGDQQHQEGKRLRRVAC
  TCPNCKEGGGRGTNLGKKKQHICHIPGCGKVYGKTSHLRAHLRWHSGERPFVCNWMYCGK
  RFTRSDELQRHRRTHTGEKKFVCPECSKRFMRSDHLAKHIKTHQNKKGIHSSSTVLASVE
  AARDDTLITAGGTTLILANIQQGSVSGIGTVNTSATSNQDILTNTEIPLQLVTVSGNETM
  E
• Function: Transcriptional factor that can act as an activator or repressor depending on isoform and/or post-translational modifications. Binds to GT and GC boxes promoter elements. Competes with SP1 for the GC-box promoters. Weak activator of transcription but can activate a number of genes involved in different processes such as cell-cycle regulation, hormone-induction and house-keeping.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: SUMOylation of transcription factors (R-HSA-3232118)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[4]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[6]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[7]
Sarcoma	DISZDG3U	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[9]
Glioma	DIS5RPEH	Disputed	Altered Expression	[10]
Leiomyosarcoma	DIS6COXM	Limited	Altered Expression	[11]
Nephropathy	DISXWP4P	Limited	Genetic Variation	[12]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[12]

6 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 Transcription factor Sp3 (SP3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor Sp3 (SP3).	[26]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription factor Sp3 (SP3).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcription factor Sp3 (SP3).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription factor Sp3 (SP3).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcription factor Sp3 (SP3).	[29]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription factor Sp3 (SP3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor Sp3 (SP3).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor Sp3 (SP3).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Transcription factor Sp3 (SP3).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor Sp3 (SP3).	[18]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Transcription factor Sp3 (SP3).	[19]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Transcription factor Sp3 (SP3).	[20]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Transcription factor Sp3 (SP3).	[21]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of Transcription factor Sp3 (SP3).	[22]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Transcription factor Sp3 (SP3).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Transcription factor Sp3 (SP3).	[8]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the activity of Transcription factor Sp3 (SP3).	[25]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Transcription factor Sp3 (SP3).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription factor Sp3 (SP3).	[27]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Transcription factor Sp3 (SP3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor Sp3 (SP3).	[32]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the activity of Transcription factor Sp3 (SP3).	[33]
Buthionine sulfoximine	DMJ46CB	Investigative	Buthionine sulfoximine increases the activity of Transcription factor Sp3 (SP3).	[25]
Nitrosoglutathione	DMZ9WI4	Investigative	Nitrosoglutathione decreases the activity of Transcription factor Sp3 (SP3).	[34]

References

• [1] The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid.Blood. 2005 Feb 1;105(3):1060-7. doi: 10.1182/blood-2003-12-4383. Epub 2004 Oct 5.
• [2] Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness.PLoS One. 2009;4(2):e4478. doi: 10.1371/journal.pone.0004478. Epub 2009 Feb 12.
• [3] The miR-491-3p/Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma.Cancer Lett. 2017 Nov 1;408:102-111. doi: 10.1016/j.canlet.2017.08.027. Epub 2017 Aug 24.
• [4] The transcription factor Sp3 regulates the expression of a metastasis-related marker of sarcoma, actin filament-associated protein 1-like 1 (AFAP1L1).PLoS One. 2013;8(1):e49709. doi: 10.1371/journal.pone.0049709. Epub 2013 Jan 9.
• [5] Sp3 expression in immune cells: a quantitative study.Lab Invest. 2002 Sep;82(9):1131-8. doi: 10.1097/01.lab.0000029149.38881.84.
• [6] Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.Nat Commun. 2018 Sep 13;9(1):3707. doi: 10.1038/s41467-018-04989-w.
• [7] Sp1 and Sp3 physically interact and co-operate with GABP for the activation of the utrophin promoter.J Mol Biol. 2001 Mar 9;306(5):985-96. doi: 10.1006/jmbi.2000.4335.
• [8] Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res. 2008 Jul 1;68(13):5345-54. doi: 10.1158/0008-5472.CAN-07-6805.
• [9] Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP.Hum Mol Genet. 2012 Mar 15;21(6):1325-35. doi: 10.1093/hmg/ddr569. Epub 2011 Dec 2.
• [10] EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas.Cancer Res. 2007 Jul 1;67(13):6121-9. doi: 10.1158/0008-5472.CAN-07-0141.
• [11] Biglycan gene expression in the human leiomyosarcoma cell line SK-UT-1. Basal and protein kinase A-induced transcription involves binding of Sp1-like/Sp3 proteins in the proximal promoter region.J Biol Chem. 1998 Oct 30;273(44):29230-40. doi: 10.1074/jbc.273.44.29230.
• [12] Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes.J Am Soc Nephrol. 2013 Oct;24(10):1537-43. doi: 10.1681/ASN.2012111122. Epub 2013 Sep 12.
• [13] Nrf2-regulated miR-380-3p Blocks the Translation of Sp3 Protein and Its Mediation of Paraquat-Induced Toxicity in Mouse Neuroblastoma N2a Cells.Toxicol Sci. 2019 Oct 1;171(2):515-529. doi: 10.1093/toxsci/kfz162.
• [14] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [15] 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.
• [16] Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression. Mol Pharmacol. 2012 Mar;81(3):455-64. doi: 10.1124/mol.111.076422. Epub 2011 Dec 15.
• [17] Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp Cell Res. 2010 Aug 1;316(13):2174-88. doi: 10.1016/j.yexcr.2010.04.027. Epub 2010 May 8.
• [18] 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.
• [19] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [20] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [21] Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer. 2011;63(7):1133-42. doi: 10.1080/01635581.2011.605984. Epub 2011 Sep 15.
• [22] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [23] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [24] Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res. 2008 Jul 1;68(13):5345-54. doi: 10.1158/0008-5472.CAN-07-6805.
• [25] Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons. Ann Neurol. 2001 Mar;49(3):345-54.
• [26] 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.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [29] 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.
• [30] Histone deacetylase 4 promotes ubiquitin-dependent proteasomal degradation of Sp3 in SH-SY5Y cells treated with di(2-ethylhexyl)phthalate (DEHP), determining neuronal death. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):190-8.
• [31] 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.
• [32] 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.
• [33] Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis. Am J Chin Med. 2008;36(5):967-80. doi: 10.1142/S0192415X08006387.
• [34] Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. Biochem J. 2004 May 15;380(Pt 1):67-74. doi: 10.1042/BJ20031687.