Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14UM8H)

• DOT Name: Protein Jumonji (JARID2)
• Synonyms: Jumonji/ARID domain-containing protein 2
• Gene Name: JARID2
• Related Disease:
  Acute monocytic leukemia
  Adult acute monocytic leukemia
  Aortic valve stenosis
  Autism spectrum disorder
  Bladder cancer
  Cardiac failure
  Cleft palate
  Colitis
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Developmental delay with variable intellectual disability and dysmorphic facies
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Epithelial ovarian cancer
  Glioma
  Isolated cleft palate
  leukaemia
  Leukemia
  Metastatic malignant neoplasm
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pervasive developmental disorder
  Primary myelofibrosis
  Prostate cancer
  Prostate carcinoma
  Rhabdomyosarcoma
  Schizophrenia
  Small lymphocytic lymphoma
  T-cell leukaemia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Tetralogy of fallot
  Syndromic intellectual disability
  Neural tube defect
  Advanced cancer
  Haematological malignancy
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Myeloproliferative neoplasm
• UniProt ID: JARD2_HUMAN
• PDB ID: 5HYN; 5LS6; 5WAI; 6C23; 6C24; 6NQ3; 6WKR; 7KSO
• Pfam ID: PF01388 ; PF02373 ; PF02375 ; PF02928
• Sequence:
  MSKERPKRNIIQKKYDDSDGIPWSEERVVRKVLYLSLKEFKNSQKRQHAEGIAGSLKTVN
  GLLGNDQSKGLGPASEQSENEKDDASQVSSTSNDVSSSDFEEGPSRKRPRLQAQRKFAQS
  QPNSPSTTPVKIVEPLLPPPATQISDLSKRKPKTEDFLTFLCLRGSPALPNSMVYFGSSQ
  DEEEVEEEDDETEDVKTATNNASSSCQSTPRKGKTHKHVHNGHVFNGSSRSTREKEPVQK
  HKSKEATPAKEKHSDHRADSRREQASANHPAAAPSTGSSAKGLAATHHHPPLHRSAQDLR
  KQVSKVNGVTRMSSLGAGVTSAKKMREVRPSPSKTVKYTATVTKGAVTYTKAKRELVKDT
  KPNHHKPSSAVNHTISGKTESSNAKTRKQVLSLGGASKSTGPAVNGLKVSGRLNPKSCTK
  EVGGRQLREGLQLREGLRNSKRRLEEAHQAEKPQSPPKKMKGAAGPAEGPGKKAPAERGL
  LNGHVKKEVPERSLERNRPKRATAGKSTPGRQAHGKADSASCENRSTSQPESVHKPQDSG
  KAEKGGGKAGWAAMDEIPVLRPSAKEFHDPLIYIESVRAQVEKFGMCRVIPPPDWRPECK
  LNDEMRFVTQIQHIHKLGRRWGPNVQRLACIKKHLKSQGITMDELPLIGGCELDLACFFR
  LINEMGGMQQVTDLKKWNKLADMLRIPRTAQDRLAKLQEAYCQYLLSYDSLSPEEHRRLE
  KEVLMEKEILEKRKGPLEGHTENDHHKFHPLPRFEPKNGLIHGVAPRNGFRSKLKEVGQA
  QLKTGRRRLFAQEKEVVKEEEEDKGVLNDFHKCIYKGRSVSLTTFYRTARNIMSMCFSKE
  PAPAEIEQEYWRLVEEKDCHVAVHCGKVDTNTHGSGFPVGKSEPFSRHGWNLTVLPNNTG
  SILRHLGAVPGVTIPWLNIGMVFSTSCWSRDQNHLPYIDYLHTGADCIWYCIPAEEENKL
  EDVVHTLLQANGTPGLQMLESNVMISPEVLCKEGIKVHRTVQQSGQFVVCFPGSFVSKVC
  CGYSVSETVHFATTQWTSMGFETAKEMKRRHIAKPFSMEKLLYQIAQAEAKKENGPTLST
  ISALLDELRDTELRQRRQLFEAGLHSSARYGSHDGSSTVADGKKKPRKWLQLETSERRCQ
  ICQHLCYLSMVVQENENVVFCLECALRHVEKQKSCRGLKLMYRYDEEQIISLVNQICGKV
  SGKNGSIENCLSKPTPKRGPRKRATVDVPPSRLSASSSSKSASSSS
• Function: Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis. Acts as an accessory subunit for the core PRC2 (Polycomb repressive complex 2) complex, which mediates histone H3K27 (H3K27me3) trimethylation on chromatin. Binds DNA and mediates the recruitment of the PRC2 complex to target genes in embryonic stem cells, thereby playing a key role in stem cell differentiation and normal embryonic development. In cardiac cells, it is required to repress expression of cyclin-D1 (CCND1) by activating methylation of 'Lys-9' of histone H3 (H3K9me) by the GLP1/EHMT1 and G9a/EHMT2 histone methyltransferases. Also acts as a transcriptional repressor of ANF via its interaction with GATA4 and NKX2-5. Participates in the negative regulation of cell proliferation signaling. Does not have histone demethylase activity.
• Tissue Specificity: During embryogenesis, predominantly expressed in neurons and particularly in dorsal root ganglion cells.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[1]
Adult acute monocytic leukemia	DISG6BLX	Strong	Biomarker	[1]
Aortic valve stenosis	DISW7AQ9	Strong	Altered Expression	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[2]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[2]
Developmental delay with variable intellectual disability and dysmorphic facies	DISYURLC	Strong	Autosomal dominant	[7]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[3]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[15]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[1]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[16]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[17]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[18]
Neural tube defect	DIS5J95E	Disputed	Genetic Variation	[19]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[14]
Haematological malignancy	DISCDP7W	Limited	Biomarker	[20]
Intellectual disability	DISMBNXP	Limited	Biomarker	[21]
Lung cancer	DISCM4YA	Limited	Biomarker	[22]
Lung carcinoma	DISTR26C	Limited	Biomarker	[22]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[20]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein Jumonji (JARID2) increases the response to substance of Arsenic trioxide.	[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 Protein Jumonji (JARID2).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Jumonji (JARID2).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein Jumonji (JARID2).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein Jumonji (JARID2).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein Jumonji (JARID2).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Jumonji (JARID2).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Protein Jumonji (JARID2).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Protein Jumonji (JARID2).	[27]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein Jumonji (JARID2).	[30]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein Jumonji (JARID2).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein Jumonji (JARID2).	[31]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Protein Jumonji (JARID2).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein Jumonji (JARID2).	[32]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Protein Jumonji (JARID2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein Jumonji (JARID2).	[35]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Protein Jumonji (JARID2).	[36]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide increases the expression of Protein Jumonji (JARID2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein Jumonji (JARID2).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Protein Jumonji (JARID2).	[34]

References

• [1] JARID2 inhibits leukemia cell proliferation by regulating CCND1 expression.Int J Hematol. 2015 Jul;102(1):76-85. doi: 10.1007/s12185-015-1797-x. Epub 2015 May 5.
• [2] Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription and reexpression of a protective fetal program.J Thorac Cardiovasc Surg. 2008 Sep;136(3):709-16. doi: 10.1016/j.jtcvs.2008.02.020. Epub 2008 Jun 9.
• [3] A study of single nucleotide polymorphisms in CD157, AIM2 and JARID2 genes in Han Chinese children with autism spectrum disorder.Nord J Psychiatry. 2018 Apr;72(3):179-183. doi: 10.1080/08039488.2017.1410570. Epub 2017 Dec 7.
• [4] Jarid2 enhances the progression of bladder cancer through regulating PTEN/AKT signaling.Life Sci. 2019 Aug 1;230:162-168. doi: 10.1016/j.lfs.2019.05.053. Epub 2019 May 21.
• [5] Brazilian multicenter study of association between polymorphisms in CRISPLD2 and JARID2 and non-syndromic oral clefts.J Oral Pathol Med. 2017 Mar;46(3):232-239. doi: 10.1111/jop.12470. Epub 2016 Jun 21.
• [6] MiR-155 contributes to Th17 cells differentiation in dextran sulfate sodium (DSS)-induced colitis mice via Jarid2.Biochem Biophys Res Commun. 2017 Jun 17;488(1):6-14. doi: 10.1016/j.bbrc.2017.04.143. Epub 2017 Apr 28.
• [7] Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability. Orphanet J Rare Dis. 2013 Jan 7;8:3. doi: 10.1186/1750-1172-8-3.
• [8] Myocardial-specific ablation of Jumonji and AT-rich interaction domain-containing 2 (Jarid2) leads to dilated cardiomyopathy in mice.J Biol Chem. 2019 Mar 29;294(13):4981-4996. doi: 10.1074/jbc.RA118.005634. Epub 2019 Jan 30.
• [9] Knockdown of JARID2 inhibits the proliferation and invasion of ovarian cancer through the PI3K/Akt signaling pathway.Mol Med Rep. 2017 Sep;16(3):3600-3605. doi: 10.3892/mmr.2017.7024. Epub 2017 Jul 17.
• [10] Reduced Expression of Jumonji AT-Rich Interactive Domain 2 (JARID2) in Glioma Inhibits Tumor Growth In Vitro and In Vivo.Oncol Res. 2017 Mar 13;25(3):365-372. doi: 10.3727/096504016X14738135889976. Epub 2016 Sep 16.
• [11] JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells.Oncogene. 2014 Feb 27;33(9):1148-57. doi: 10.1038/onc.2013.46. Epub 2013 Feb 25.
• [12] Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia.Mol Cell Proteomics. 2018 Feb;17(2):290-303. doi: 10.1074/mcp.RA117.000425. Epub 2017 Dec 1.
• [13] miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis.Blood. 2014 Sep 25;124(13):e21-32. doi: 10.1182/blood-2013-12-544197. Epub 2014 Aug 5.
• [14] Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.Oncogenesis. 2019 Feb 19;8(3):14. doi: 10.1038/s41389-019-0122-6.
• [15] Whole genome association study in a homogenous population in Shandong peninsula of China reveals JARID2 as a susceptibility gene for schizophrenia.J Biomed Biotechnol. 2009;2009:536918. doi: 10.1155/2009/536918. Epub 2009 Oct 27.
• [16] A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia.Genes Dev. 2012 Apr 1;26(7):651-6. doi: 10.1101/gad.186411.111. Epub 2012 Mar 19.
• [17] miRNA-940 reduction contributes to human Tetralogy of Fallot development.J Cell Mol Med. 2014 Sep;18(9):1830-9. doi: 10.1111/jcmm.12309. Epub 2014 Jun 1.
• [18] JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. Genet Med. 2021 Feb;23(2):374-383. doi: 10.1038/s41436-020-00992-z. Epub 2020 Oct 20.
• [19] Gene and microRNA expression in p53-deficient day 8.5 mouse embryos.Birth Defects Res A Clin Mol Teratol. 2009 Jun;85(6):546-55. doi: 10.1002/bdra.20565.
• [20] JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells.Cancer Cell. 2018 Nov 12;34(5):741-756.e8. doi: 10.1016/j.ccell.2018.10.008.
• [21] Intragenic CNVs for epigenetic regulatory genes in intellectual disability: Survey identifies pathogenic and benign single exon changes.Am J Med Genet A. 2016 Nov;170(11):2916-2926. doi: 10.1002/ajmg.a.37669.
• [22] MEG3 Long Noncoding RNA Contributes to the Epigenetic Regulation of Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines.J Biol Chem. 2017 Jan 6;292(1):82-99. doi: 10.1074/jbc.M116.750950. Epub 2016 Nov 16.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Differential responses to retinoic acid and endocrine disruptor compounds of subpopulations within human embryonic stem cell lines. Differentiation. 2012 Nov;84(4):330-43. doi: 10.1016/j.diff.2012.07.006. Epub 2012 Aug 18.
• [25] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [26] 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.
• [27] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [28] 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.
• [29] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [30] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [36] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [37] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.