Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG4ADLM)

• DOT Name: Homeobox protein Meis2 (MEIS2)
• Synonyms: Meis1-related protein 1
• Gene Name: MEIS2
• Related Disease:
  Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies
  Syndromic intellectual disability
  Acute myelogenous leukaemia
  Advanced cancer
  Amoebiasis
  Benign prostatic hyperplasia
  Heart septal defect
  Hepatocellular carcinoma
  Intellectual disability
  Intestinal amebiasis
  leukaemia
  Leukemia
  Myocardial infarction
  Neoplasm
  Obsessive compulsive disorder
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Retinitis pigmentosa
  Ventricular septal defect
  Cleft palate
  Gastroesophageal reflux disease
  Isolated cleft palate
  Plasma cell myeloma
  Tetralogy of fallot
  Bladder cancer
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Neuroblastoma
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: MEIS2_HUMAN
• PDB ID: 3K2A; 4XRM; 5BNG; 5EG0
• Pfam ID: PF05920 ; PF16493
• Sequence:
  MAQRYDELPHYGGMDGVGVPASMYGDPHAPRPIPPVHHLNHGPPLHATQHYGAHAPHPNV
  MPASMGSAVNDALKRDKDAIYGHPLFPLLALVFEKCELATCTPREPGVAGGDVCSSDSFN
  EDIAVFAKQVRAEKPLFSSNPELDNLMIQAIQVLRFHLLELEKVHELCDNFCHRYISCLK
  GKMPIDLVIDERDGSSKSDHEELSGSSTNLADHNPSSWRDHDDATSTHSAGTPGPSSGGH
  ASQSGDNSSEQGDGLDNSVASPGTGDDDDPDKDKKRQKKRGIFPKVATNIMRAWLFQHLT
  HPYPSEEQKKQLAQDTGLTILQVNNWFINARRRIVQPMIDQSNRAGFLLDPSVSQGAAYS
  PEGQPMGSFVLDGQQHMGIRPAGLQSMPGDYVSQGGPMGMSMAQPSYTPPQMTPHPTQLR
  HGPPMHSYLPSHPHHPAMMMHGGPPTHPGMTMSAQSPTMLNSVDPNVGGQVMDIHAQ
• Function: Involved in transcriptional regulation. Binds to HOX or PBX proteins to form dimers, or to a DNA-bound dimer of PBX and HOX proteins and thought to have a role in stabilization of the homeoprotein-DNA complex. Isoform 3 is required for the activity of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element; MEIS2 is not involved in complex DNA-binding. Probably in complex with PBX1, is involved in transcriptional regulation by KLF4. Isoform 3 and isoform 4 can bind to a EPHA8 promoter sequence containing the DNA motif 5'-CGGTCA-3'; in cooperation with a PBX protein (such as PBX2) is proposed to be involved in the transcriptional activation of EPHA8 in the developing midbrain. May be involved in regulation of myeloid differentiation. Can bind to the DNA sequence 5'-TGACAG-3'in the activator ACT sequence of the D(1A) dopamine receptor (DRD1) promoter and activate DRD1 transcription; isoform 5 cannot activate DRD1 transcription.
• Tissue Specificity: Expressed in various tissues. Expressed at high level in the lymphoid organs of hematopoietic tissues. Also expressed in some regions of the brain, such as the putamen.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies	DISP6AXI	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Amoebiasis	DISAJWJL	Strong	Genetic Variation	[5]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[6]
Heart septal defect	DISQ5C5J	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Intestinal amebiasis	DIS0IHMD	Strong	Genetic Variation	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Myocardial infarction	DIS655KI	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Posttranslational Modification	[6]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[13]
Cleft palate	DIS6G5TF	moderate	Genetic Variation	[8]
Gastroesophageal reflux disease	DISQ8G5S	moderate	Biomarker	[1]
Isolated cleft palate	DISV80CD	moderate	Genetic Variation	[8]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[14]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[15]
Bladder cancer	DISUHNM0	Limited	Biomarker	[16]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[17]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[18]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[19]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[16]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Homeobox protein Meis2 (MEIS2) increases the response to substance of Arsenic.	[38]

20 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 Homeobox protein Meis2 (MEIS2).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein Meis2 (MEIS2).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Meis2 (MEIS2).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein Meis2 (MEIS2).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeobox protein Meis2 (MEIS2).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homeobox protein Meis2 (MEIS2).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein Meis2 (MEIS2).	[26]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Homeobox protein Meis2 (MEIS2).	[27]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein Meis2 (MEIS2).	[28]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Homeobox protein Meis2 (MEIS2).	[29]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Homeobox protein Meis2 (MEIS2).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Homeobox protein Meis2 (MEIS2).	[31]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Homeobox protein Meis2 (MEIS2).	[22]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Homeobox protein Meis2 (MEIS2).	[22]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Homeobox protein Meis2 (MEIS2).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Meis2 (MEIS2).	[33]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Homeobox protein Meis2 (MEIS2).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeobox protein Meis2 (MEIS2).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeobox protein Meis2 (MEIS2).	[37]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Homeobox protein Meis2 (MEIS2).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Homeobox protein Meis2 (MEIS2).	[32]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Homeobox protein Meis2 (MEIS2).	[36]

References

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• [3] MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML.Cell Rep. 2016 Jul 12;16(2):498-507. doi: 10.1016/j.celrep.2016.05.094. Epub 2016 Jun 23.
• [4] MEIS2 promotes cell migration and invasion in colorectal cancer.Oncol Rep. 2019 Jul;42(1):213-223. doi: 10.3892/or.2019.7161. Epub 2019 May 15.
• [5] Molecular mechanisms underlying gliomas and glioblastoma pathogenesis revealed by bioinformatics analysis of microarray data.Med Oncol. 2017 Sep 26;34(11):182. doi: 10.1007/s12032-017-1043-x.
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• [7] MEIS2C and MEIS2D promote tumor progression via Wnt/-catenin and hippo/YAP signaling in hepatocellular carcinoma.J Exp Clin Cancer Res. 2019 Oct 17;38(1):417. doi: 10.1186/s13046-019-1417-3.
• [8] MEIS2 gene is responsible for intellectual disability, cardiac defects and a distinct facial phenotype.Eur J Med Genet. 2020 Jan;63(1):103627. doi: 10.1016/j.ejmg.2019.01.017. Epub 2019 Feb 5.
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• [10] Inhibition of Senescence-Associated Genes Rb1 and Meis2 in Adult Cardiomyocytes Results in Cell Cycle Reentry and Cardiac Repair Post-Myocardial Infarction.J Am Heart Assoc. 2019 Aug 6;8(15):e012089. doi: 10.1161/JAHA.119.012089. Epub 2019 Jul 18.
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• [15] Prenatal diagnosis and molecular cytogenetic characterization of a de novo 4.858-Mb microdeletion in 15q14 associated with ACTC1 and MEIS2 haploinsufficiency and tetralogy of Fallot.Taiwan J Obstet Gynecol. 2016 Apr;55(2):270-4. doi: 10.1016/j.tjog.2016.02.013.
• [16] Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM.Cancer Lett. 2019 May 1;449:31-44. doi: 10.1016/j.canlet.2019.01.041. Epub 2019 Feb 10.
• [17] A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance.Mol Cell. 2017 Jan 5;65(1):154-167. doi: 10.1016/j.molcel.2016.11.034. Epub 2016 Dec 29.
• [18] Hypermethylated and downregulated MEIS2 are involved in stemness properties and oxaliplatin-based chemotherapy resistance of colorectal cancer.J Cell Physiol. 2019 Aug;234(10):18180-18191. doi: 10.1002/jcp.28451. Epub 2019 Mar 11.
• [19] Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma.Cancer Res. 2018 Apr 15;78(8):1935-1947. doi: 10.1158/0008-5472.CAN-17-1860. Epub 2018 Jan 30.
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• [34] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [35] 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.
• [36] 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.
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• [38] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.