Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWB30IZ)

• DOT Name: Transcription factor Sp4 (SP4)
• Synonyms: SPR-1
• Gene Name: SP4
• Related Disease:
  Bipolar depression
  Bipolar disorder
  Colon cancer
  Colon carcinoma
  Major depressive disorder
  Non-alcoholic fatty liver disease
  Schizophrenia
  Urinary bladder neoplasm
  Advanced cancer
  Colonic neoplasm
  Cone-rod dystrophy 2
  Leber congenital amaurosis
  Mental disorder
• UniProt ID: SP4_HUMAN
• Pfam ID: PF00096
• Sequence:
  MSDQKKEEEEEAAAAAAMATEGGKTSEPENNNKKPKTSGSQDSQPSPLALLAATCSKIGT
  PGENQATGQQQIIIDPSQGLVQLQNQPQQLELVTTQLAGNAWQLVASTPPASKENNVSQP
  ASSSSSSSSSNNGSASPTKTKSGNSSTPGQFQVIQVQNPSGSVQYQVIPQLQTVEGQQIQ
  INPTSSSSLQDLQGQIQLISAGNNQAILTAANRTASGNILAQNLANQTVPVQIRPGVSIP
  LQLQTLPGTQAQVVTTLPINIGGVTLALPVINNVAAGGGTGQVGQPAATADSGTSNGNQL
  VSTPTNTTTSASTMPESPSSSTTCTTTASTSLTSSDTLVSSADTGQYASTSASSSERTIE
  ESQTPAATESEAQSSSQLQPNGMQNAQDQSNSLQQVQIVGQPILQQIQIQQPQQQIIQAI
  PPQSFQLQSGQTIQTIQQQPLQNVQLQAVNPTQVLIRAPTLTPSGQISWQTVQVQNIQSL
  SNLQVQNAGLSQQLTITPVSSSGGTTLAQIAPVAVAGAPITLNTAQLASVPNLQTVSVAN
  LGAAGVQVQGVPVTITSVAGQQQGQDGVKVQQATIAPVTVAVGGIANATIGAVSPDQLTQ
  VHLQQGQQTSDQEVQPGKRLRRVACSCPNCREGEGRGSNEPGKKKQHICHIEGCGKVYGK
  TSHLRAHLRWHTGERPFICNWMFCGKRFTRSDELQRHRRTHTGEKRFECPECSKRFMRSD
  HLSKHVKTHQNKKGGGTALAIVTSGELDSSVTEVLGSPRIVTVAAISQDSNPATPNVSTN
  MEEF
• Function: Binds to GT and GC boxes promoters elements. Probable transcriptional activator.
• Tissue Specificity: Abundant in brain.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar depression	DISA75FU	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[4]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[8]
Colonic neoplasm	DISSZ04P	moderate	Altered Expression	[8]
Cone-rod dystrophy 2	DISX2RWY	moderate	Genetic Variation	[9]
Leber congenital amaurosis	DISMGH8F	moderate	Genetic Variation	[9]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[10]

3 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 Sp4 (SP4).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Transcription factor Sp4 (SP4).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Transcription factor Sp4 (SP4).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription factor Sp4 (SP4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription factor Sp4 (SP4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription factor Sp4 (SP4).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor Sp4 (SP4).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Transcription factor Sp4 (SP4).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcription factor Sp4 (SP4).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor Sp4 (SP4).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transcription factor Sp4 (SP4).	[16]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Transcription factor Sp4 (SP4).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription factor Sp4 (SP4).	[19]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Transcription factor Sp4 (SP4).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription factor Sp4 (SP4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription factor Sp4 (SP4).	[22]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Transcription factor Sp4 (SP4).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription factor Sp4 (SP4).	[25]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Transcription factor Sp4 (SP4).	[26]

References

• [1] Transcription factor SP4 is a susceptibility gene for bipolar disorder.PLoS One. 2009;4(4):e5196. doi: 10.1371/journal.pone.0005196. Epub 2009 Apr 9.
• [2] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [3] Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins.Mol Pharmacol. 2005 Aug;68(2):317-29. doi: 10.1124/mol.105.011825. Epub 2005 May 9.
• [4] Role played by the SP4 gene in schizophrenia and major depressive disorder in the Han Chinese population.Br J Psychiatry. 2016 May;208(5):441-5. doi: 10.1192/bjp.bp.114.151688. Epub 2015 Oct 8.
• [5] GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network.BMC Med. 2019 Jul 17;17(1):135. doi: 10.1186/s12916-019-1364-z.
• [6] Specificity proteins 1 and 4 in peripheral blood mononuclear cells in postmenopausal women with schizophrenia: a 24-week double-blind, randomized, parallel, placebo-controlled trial.Eur Arch Psychiatry Clin Neurosci. 2019 Dec;269(8):941-948. doi: 10.1007/s00406-018-0938-7. Epub 2018 Aug 30.
• [7] 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.
• [8] 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.
• [9] Association of the Asn306Ser variant of the SP4 transcription factor and an intronic variant in the beta-subunit of transducin with digenic disease.Mol Vis. 2007 Feb 28;13:287-92.
• [10] Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders.Hum Mol Genet. 2010 Oct 1;19(19):3797-805. doi: 10.1093/hmg/ddq298. Epub 2010 Jul 15.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] 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.
• [13] 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.
• [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] 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.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] 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.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [22] 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.
• [23] 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.
• [24] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [25] 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.
• [26] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.