Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3QT3L)

• DOT Name: Transcription factor HIVEP3 (HIVEP3)
• Synonyms: Human immunodeficiency virus type I enhancer-binding protein 3; Kappa-B and V(D)J recombination signal sequences-binding protein; Kappa-binding protein 1; KBP-1; Zinc finger protein ZAS3
• Gene Name: HIVEP3
• Related Disease:
  Gastric neoplasm
  Neoplasm
  Neurodevelopmental disorder
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Lupus
  Parkinson disease
  Renal cell carcinoma
  Systemic lupus erythematosus
  Advanced cancer
  Rheumatoid arthritis
  Acute myelogenous leukaemia
  Osteoporosis
• UniProt ID: ZEP3_HUMAN
• Pfam ID: PF00096
• Sequence:
  MDPEQSVKGTKKAEGSPRKRLTKGEAIQTSVSSSVPYPGSGTAATQESPAQELLAPQPFP
  GPSSVLREGSQEKTGQQQKPPKRPPIEASVHISQLPQHPLTPAFMSPGKPEHLLEGSTWQ
  LVDPMRPGPSGSFVAPGLHPQSQLLPSHASIIPPEDLPGVPKVFVPRPSQVSLKPTEEAH
  KKERKPQKPGKYICQYCSRPCAKPSVLQKHIRSHTGERPYPCGPCGFSFKTKSNLYKHRK
  SHAHRIKAGLASGMGGEMYPHGLEMERIPGEEFEEPTEGESTDSEEETSATSGHPAELSP
  RPKQPLLSSGLYSSGSHSSSHERCSLSQSSTAQSLEDPPPFVEPSSEHPLSHKPEDTHTI
  KQKLALRLSERKKVIDEQAFLSPGSKGSTESGYFSRSESAEQQVSPPNTNAKSYAEIIFG
  KCGRIGQRTAMLTATSTQPLLPLSTEDKPSLVPLSVPRTQVIEHITKLITINEAVVDTSE
  IDSVKPRRSSLSRRSSMESPKSSLYREPLSSHSEKTKPEQSLLSLQHPPSTAPPVPLLRS
  HSMPSAACTISTPHHPFRGSYSFDDHITDSEALSHSSHVFTSHPRMLKRQPAIELPLGGE
  YSSEEPGPSSKDTASKPSDEVEPKESELTKKTKKGLKTKGVIYECNICGARYKKRDNYEA
  HKKYYCSELQIAKPISAGTHTSPEAEKSQIEHEPWSQMMHYKLGTTLELTPLRKRRKEKS
  LGDEEEPPAFESTKSQFGSPGPSDAARNLPLESTKSPAEPSKSVPSLEGPTGFQPRTPKP
  GSGSESGKERRTTSKEISVIQHTSSFEKSDSLEQPSGLEGEDKPLAQFPSPPPAPHGRSA
  HSLQPKLVRQPNIQVPEILVTEEPDRPDTEPEPPPKEPEKTEEFQWPQRSQTLAQLPAEK
  LPPKKKRLRLAEMAQSSGESSFESSVPLSRSPSQESNVSLSGSSRSASFERDDHGKAEAP
  SPSSDMRPKPLGTHMLTVPSHHPHAREMRRSASEQSPNVSHSAHMTETRSKSFDYGSLSL
  TGPSAPAPVAPPARVAPPERRKCFLVRQASLSRPPESELEVAPKGRQESEEPQPSSSKPS
  AKSSLSQISSAATSHGGPPGGKGPGQDRPPLGPTVPYTEALQVFHHPVAQTPLHEKPYLP
  PPVSLFSFQHLVQHEPGQSPEFFSTQAMSSLLSSPYSMPPLPPSLFQAPPLPLQPTVLHP
  GQLHLPQLMPHPANIPFRQPPSFLPMPYPTSSALSSGFFLPLQSQFALQLPGDVESHLPQ
  IKTSLAPLATGSAGLSPSTEYSSDIRLPPVAPPASSSAPTSAPPLALPACPDTMVSLVVP
  VRVQTNMPSYGSAMYTTLSQILVTQSQGSSATVALPKFEEPPSKGTTVCGADVHEVGPGP
  SGLSEEQSRAFPTPYLRVPVTLPERKGTSLSSESILSLEGSSSTAGGSKRVLSPAGSLEL
  TMETQQQKRVKEEEASKADEKLELVKPCSVVLTSTEDGKRPEKSHLGNQGQGRRELEMLS
  SLSSDPSDTKEIPPLPHPALSHGTAPGSEALKEYPQPSGKPHRRGLTPLSVKKEDSKEQP
  DLPSLAPPSSLPLSETSSRPAKSQEGTDSKKVLQFPSLHTTTNVSWCYLNYIKPNHIQHA
  DRRSSVYAGWCISLYNPNLPGVSTKAALSLLRSKQKVSKETYTMATAPHPEAGRLVPSSS
  RKPRMTEVHLPSLVSPEGQKDLARVEKEEERRGEPEEDAPASQRGEPARIKIFEGGYKSN
  EEYVYVRGRGRGKYVCEECGIRCKKPSMLKKHIRTHTDVRPYVCKHCHFAFKTKGNLTKH
  MKSKAHSKKCQETGVLEELEAEEGTSDDLFQDSEGREGSEAVEEHQFSDLEDSDSDSDLD
  EDEDEDEEESQDELSRPSSEAPPPGPPHALRADSSPILGPQPPDAPASGTEATRGSSVSE
  AERLTASSCSMSSQSMPGLPWLGPAPLGSVEKDTGSALSYKPVSPRRPWSPSKEAGSRPP
  LARKHSLTKNDSSPQRCSPAREPQASAPSPPGLHVDPGRGMGALPCGSPRLQLSPLTLCP
  LGRELAPRAHVLSKLEGTTDPGLPRYSPTRRWSPGQAESPPRSAPPGKWALAGPGSPSAG
  EHGPGLGLDPRVLFPPAPLPHKLLSRSPETCASPWQKAESRSPSCSPGPAHPLSSRPFSA
  LHDFHGHILARTEENIFSHLPLHSQHLTRAPCPLIPIGGIQMVQARPGAHPTLLPGPTAA
  WVSGFSGGGSDLTGAREAQERGRWSPTESSSASVSPVAKVSKFTLSSELEGGDYPKERER
  TGGGPGRPPDWTPHGTGAPAEPTPTHSPCTPPDTLPRPPQGRRAAQSWSPRLESPRAPTN
  PEPSATPPLDRSSSVGCLAEASARFPARTRNLSGEPRTRQDSPKPSGSGEPRAHPHQPED
  RVPPNA
• Function: Plays a role of transcription factor; binds to recognition signal sequences (Rss heptamer) for somatic recombination of immunoglobulin and T-cell receptor gene segments; Binds also to the kappa-B motif of gene such as S100A4, involved in cell progression and differentiation. Kappa-B motif is a gene regulatory element found in promoters and enhancers of genes involved in immunity, inflammation, and growth and that responds to viral antigens, mitogens, and cytokines. Involvement of HIVEP3 in cell growth is strengthened by the fact that its down-regulation promotes cell cycle progression with ultimate formation of multinucleated giant cells. Strongly inhibits TNF-alpha-induced NF-kappa-B activation; Interferes with nuclear factor NF-kappa-B by several mechanisms: as transcription factor, by competing for Kappa-B motif and by repressing transcription in the nucleus; through a non transcriptional process, by inhibiting nuclear translocation of RELA by association with TRAF2, an adapter molecule in the tumor necrosis factor signaling, which blocks the formation of IKK complex. Interaction with TRAF proteins inhibits both NF-Kappa-B-mediated and c-Jun N-terminal kinase/JNK-mediated responses that include apoptosis and pro-inflammatory cytokine gene expression. Positively regulates the expression of IL2 in T-cell. Essential regulator of adult bone formation.
• Reactome Pathway: Regulation of RUNX2 expression and activity (R-HSA-8939902)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Lupus	DISOKJWA	Strong	Altered Expression	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Osteoporosis	DISF2JE0	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transcription factor HIVEP3 (HIVEP3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription factor HIVEP3 (HIVEP3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor HIVEP3 (HIVEP3).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transcription factor HIVEP3 (HIVEP3).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Transcription factor HIVEP3 (HIVEP3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription factor HIVEP3 (HIVEP3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor HIVEP3 (HIVEP3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcription factor HIVEP3 (HIVEP3).	[21]

References

• [1] Novel c-Met inhibitor suppresses the growth of c-Met-addicted gastric cancer cells.BMC Cancer. 2016 Jan 22;16:35. doi: 10.1186/s12885-016-2058-y.
• [2] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [3] Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus.Mol Immunol. 2013 May;54(1):23-31. doi: 10.1016/j.molimm.2012.10.026. Epub 2012 Nov 22.
• [4] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [5] Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene.Oncogene. 2004 Aug 5;23(35):5941-9. doi: 10.1038/sj.onc.1207789.
• [6] Association mapping of the PARK10 region for Parkinson's disease susceptibility genes.Parkinsonism Relat Disord. 2014 Jan;20(1):93-8. doi: 10.1016/j.parkreldis.2013.10.001. Epub 2013 Oct 11.
• [7] Tissue-specificity of heparan sulfate biosynthetic machinery in cancer.Cell Adh Migr. 2015;9(6):452-9. doi: 10.1080/19336918.2015.1049801.
• [8] Increased sensitivity of rheumatoid synoviocytes to Schnurri-3 expression in TNF- and IL-17A induced osteoblastic differentiation.Bone. 2016 Jun;87:89-96. doi: 10.1016/j.bone.2016.04.008. Epub 2016 Apr 9.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis.Nat Commun. 2019 Jul 4;10(1):2958. doi: 10.1038/s41467-019-10809-6.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] 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.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] 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.
• [21] 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.
• [22] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [23] 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.