Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT63JZCI)

• DOT Name: Protein arginine N-methyltransferase 2 (PRMT2)
• Synonyms: EC 2.1.1.319; Histone-arginine N-methyltransferase PRMT2
• Gene Name: PRMT2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Asthma
  Breast neoplasm
  Estrogen-receptor positive breast cancer
  Glioblastoma multiforme
  Polyarteritis nodosa
  Vasculitis due to ADA2 deficiency
  Breast cancer
  Breast carcinoma
• UniProt ID: ANM2_HUMAN
• PDB ID: 1X2P
• EC Number: 2.1.1.319
• Pfam ID: PF05175 ; PF00018
• Sequence:
  MATSGDCPRSESQGEEPAECSEAGLLQEGVQPEEFVAIADYAATDETQLSFLRGEKILIL
  RQTTADWWWGERAGCCGYIPANHVGKHVDEYDPEDTWQDEEYFGSYGTLKLHLEMLADQP
  RTTKYHSVILQNKESLTDKVILDVGCGTGIISLFCAHYARPRAVYAVEASEMAQHTGQLV
  LQNGFADIITVYQQKVEDVVLPEKVDVLVSEWMGTCLLFEFMIESILYARDAWLKEDGVI
  WPTMAALHLVPCSADKDYRSKVLFWDNAYEFNLSALKSLAVKEFFSKPKYNHILKPEDCL
  SEPCTILQLDMRTVQISDLETLRGELRFDIRKAGTLHGFTAWFSVHFQSLQEGQPPQVLS
  TGPFHPTTHWKQTLFMMDDPVPVHTGDVVTGSVVLQRNPVWRRHMSVALSWAVTSRQDPT
  SQKVGEKVFPIWR
• Function: Arginine methyltransferase that methylates the guanidino nitrogens of arginyl residues in proteins such as STAT3, FBL, histone H4. Acts as a coactivator (with NCOA2) of the androgen receptor (AR)-mediated transactivation. Acts as a coactivator (with estrogen) of estrogen receptor (ER)-mediated transactivation. Enhances PGR, PPARG, RARA-mediated transactivation. May inhibit NF-kappa-B transcription and promote apoptosis. Represses E2F1 transcriptional activity (in a RB1-dependent manner). May be involved in growth regulation.
• Tissue Specificity: Widely expressed. Highly expressed in androgen target organs such as heart, prostate, skeletal muscle, ovary and spinal cord.
• BioCyc Pathway: MetaCyc:HS08486-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Asthma	DISW9QNS	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Polyarteritis nodosa	DISRQ5X8	Strong	Biomarker	[4]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[5]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[5]

19 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 arginine N-methyltransferase 2 (PRMT2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[14]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[13]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[19]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[22]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Protein arginine N-methyltransferase 2 (PRMT2).	[23]

1 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 Protein arginine N-methyltransferase 2 (PRMT2).	[17]

References

• [1] PRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastoma.Nat Commun. 2018 Oct 31;9(1):4552. doi: 10.1038/s41467-018-06968-7.
• [2] [Expression of protein arginine N-methyltransferases in E3 rat models of acute asthma].Nan Fang Yi Ke Da Xue Xue Bao. 2010 Apr;30(4):716-9.
• [3] PRMT2, a C-terminal splice variant of PRMT2, inhibits the growth of breast cancer cells.Oncol Rep. 2017 Aug;38(2):1303-1311. doi: 10.3892/or.2017.5786. Epub 2017 Jul 3.
• [4] PRMT2 and ROR expression are associated with breast cancer survival outcomes.Mol Endocrinol. 2014 Jul;28(7):1166-85. doi: 10.1210/me.2013-1403. Epub 2014 Jun 9.
• [5] Protein arginine N-methyltransferase2 reverses tamoxifen resistance in breast cancer cells through suppression of ER-36.Oncol Rep. 2018 Jun;39(6):2604-2612. doi: 10.3892/or.2018.6350. Epub 2018 Apr 2.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [16] 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.
• [17] 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.
• [18] Ribavirin inhibits the growth and ascites formation of hepatocellular carcinoma through downregulation of type I CARM1 and type II PRMT5. Toxicol Appl Pharmacol. 2022 Jan 15;435:115829. doi: 10.1016/j.taap.2021.115829. Epub 2021 Dec 14.
• [19] 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.
• [20] 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.
• [21] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.