Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WMVM4)

• DOT Name: Pre-B-cell leukemia transcription factor 3 (PBX3)
• Synonyms: Homeobox protein PBX3
• Gene Name: PBX3
• Related Disease:
  Melanoma
  Acute myelogenous leukaemia
  Acute undifferentiated leukemia
  Adult hepatocellular carcinoma
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Coeliac disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Dental caries
  Gastric cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Leiomyoma
  leukaemia
  Leukemia
  Metastatic malignant neoplasm
  Neoplasm
  Plasma cell myeloma
  Stomach cancer
  Uterine fibroids
  Glioma
  Pancreatic cancer
  Tetralogy of fallot
  Liver cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: PBX3_HUMAN
• Pfam ID: PF05920 ; PF03792
• Sequence:
  MDDQSRMLQTLAGVNLAGHSVQGGMALPPPPHGHEGADGDGRKQDIGDILHQIMTITDQS
  LDEAQAKKHALNCHRMKPALFSVLCEIKEKTGLSIRGAQEEDPPDPQLMRLDNMLLAEGV
  SGPEKGGGSAAAAAAAAASGGSSDNSIEHSDYRAKLTQIRQIYHTELEKYEQACNEFTTH
  VMNLLREQSRTRPISPKEIERMVGIIHRKFSSIQMQLKQSTCEAVMILRSRFLDARRKRR
  NFSKQATEILNEYFYSHLSNPYPSEEAKEELAKKCSITVSQVSNWFGNKRIRYKKNIGKF
  QEEANLYAAKTAVTAAHAVAAAVQNNQTNSPTTPNSGSSGSFNLPNSGDMFMNMQSLNGD
  SYQGSQVGANVQSQVDTLRHVINQTGGYSDGLGGNSLYSPHNLNANGGWQDATTPSSVTS
  PTEGPGSVHSDTSN
• Function: Transcriptional activator that binds the sequence 5'-ATCAATCAA-3'.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Acute undifferentiated leukemia	DISJ4SSG	Strong	Biomarker	[3]
Adult hepatocellular carcinoma	DIS6ZPAI	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Coeliac disease	DISIY60C	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Posttranslational Modification	[8]
Colon carcinoma	DISJYKUO	Strong	Posttranslational Modification	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Posttranslational Modification	[8]
Dental caries	DISRBCMD	Strong	Genetic Variation	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[12]
leukaemia	DISS7D1V	Strong	Genetic Variation	[3]
Leukemia	DISNAKFL	Strong	Genetic Variation	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[14]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
Glioma	DIS5RPEH	moderate	Altered Expression	[11]
Pancreatic cancer	DISJC981	moderate	Biomarker	[15]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[16]
Liver cancer	DISDE4BI	Limited	Altered Expression	[5]
Prostate cancer	DISF190Y	Limited	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Pre-B-cell leukemia transcription factor 3 (PBX3) affects the response to substance of Fluorouracil.	[37]

17 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 Pre-B-cell leukemia transcription factor 3 (PBX3).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[25]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[27]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[29]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[33]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Pre-B-cell leukemia transcription factor 3 (PBX3).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Pre-B-cell leukemia transcription factor 3 (PBX3).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pre-B-cell leukemia transcription factor 3 (PBX3).	[32]

References

• [1] miR-495 inhibits proliferation, migration, and invasion and induces apoptosis via inhibiting PBX3 in melanoma cells.Onco Targets Ther. 2018 Apr 5;11:1909-1920. doi: 10.2147/OTT.S152362. eCollection 2018.
• [2] Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival.Theranostics. 2018 Jul 30;8(16):4359-4371. doi: 10.7150/thno.26900. eCollection 2018.
• [3] PBX3 is essential for leukemia stem cell maintenance in MLL-rearranged leukemia.Int J Cancer. 2017 Jul 15;141(2):324-335. doi: 10.1002/ijc.30739. Epub 2017 May 8.
• [4] MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma.Oncotarget. 2016 Jul 5;7(27):42461-42473. doi: 10.18632/oncotarget.9886.
• [5] miR-302a inhibits human HepG2 and SMMC-7721 cells proliferation and promotes apoptosis by targeting MAP3K2 and PBX3.Sci Rep. 2019 Feb 14;9(1):2032. doi: 10.1038/s41598-018-38435-0.
• [6] PBX3 is associated with proliferation and poor prognosis in patients with cervical cancer.Onco Targets Ther. 2017 Nov 27;10:5685-5694. doi: 10.2147/OTT.S150139. eCollection 2017.
• [7] Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample.Genes Immun. 2009 Oct;10(7):659-61. doi: 10.1038/gene.2009.54. Epub 2009 Jul 23.
• [8] PBX3 hypermethylation in peripheral blood leukocytes predicts better prognosis in colorectal cancer: A propensity score analysis.Cancer Med. 2019 Jul;8(8):4001-4011. doi: 10.1002/cam4.2321. Epub 2019 May 29.
• [9] Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.
• [10] MicroRNA-320a suppresses tumor progression by targeting PBX3 in gastric cancer and is downregulated by DNA methylation.World J Gastrointest Oncol. 2019 Oct 15;11(10):842-856. doi: 10.4251/wjgo.v11.i10.842.
• [11] PBX3/MEK/ERK1/2/LIN28/let-7b positive feedback loop enhances mesenchymal phenotype to promote glioblastoma migration and invasion.J Exp Clin Cancer Res. 2018 Jul 17;37(1):158. doi: 10.1186/s13046-018-0841-0.
• [12] Genetic heterogeneity in leiomyomas of deep soft tissue.Oncotarget. 2017 Jul 25;8(30):48769-48781. doi: 10.18632/oncotarget.17953.
• [13] EWSR1-PBX3 gene fusion in cutaneous syncytial myoepithelioma.J Cutan Pathol. 2019 Jun;46(6):421-424. doi: 10.1111/cup.13450. Epub 2019 Apr 3.
• [14] miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3.Biochem Biophys Res Commun. 2016 May 13;473(4):1315-1320. doi: 10.1016/j.bbrc.2016.04.069. Epub 2016 Apr 14.
• [15] miR-129-5p suppresses proliferation, migration, and induces apoptosis in pancreatic cancer cells by targeting PBX3.Acta Biochim Biophys Sin (Shanghai). 2019 Sep 6;51(10):997-1007. doi: 10.1093/abbs/gmz096.
• [16] Pbx/Meis deficiencies demonstrate multigenetic origins of congenital heart disease.Circ Res. 2008 Sep 26;103(7):702-9. doi: 10.1161/CIRCRESAHA.108.175489. Epub 2008 Aug 21.
• [17] Regulation of PBX3 expression by androgen and Let-7d in prostate cancer.Mol Cancer. 2011 May 6;10:50. doi: 10.1186/1476-4598-10-50.
• [18] 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.
• [19] 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.
• [20] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] 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.
• [23] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [24] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] 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.
• [28] 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.
• [29] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [30] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] 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.
• [33] 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.
• [34] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [35] 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.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [37] 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.