Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5V3XIN)

• DOT Name: Protein arginine N-methyltransferase 6 (PRMT6)
• Synonyms: EC 2.1.1.319; Heterogeneous nuclear ribonucleoprotein methyltransferase-like protein 6; Histone-arginine N-methyltransferase PRMT6
• Gene Name: PRMT6
• Related Disease:
  Gastric cancer
  Stomach cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiovascular disease
  Cocaine addiction
  HIV infectious disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Metabolic disorder
  Neoplasm
  Obesity
  Oligospermia
  Osteosarcoma
  Severe combined immunodeficiency
  B-cell neoplasm
  Hepatocellular carcinoma
  Pulmonary emphysema
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Colonic neoplasm
  Kennedy disease
• UniProt ID: ANM6_HUMAN
• PDB ID: 4HC4; 4QPP; 4QQK; 4Y2H; 4Y30; 5E8R; 5EGS; 5HZM; 5WCF; 6P7I; 6W6D; 6WAD; 7NR4
• EC Number: 2.1.1.319
• Pfam ID: PF13649
• Sequence:
  MSQPKKRKLESGGGGEGGEGTEEEDGAEREAALERPRRTKRERDQLYYECYSDVSVHEEM
  IADRVRTDAYRLGILRNWAALRGKTVLDVGAGTGILSIFCAQAGARRVYAVEASAIWQQA
  REVVRFNGLEDRVHVLPGPVETVELPEQVDAIVSEWMGYGLLHESMLSSVLHARTKWLKE
  GGLLLPASAELFIAPISDQMLEWRLGFWSQVKQHYGVDMSCLEGFATRCLMGHSEIVVQG
  LSGEDVLARPQRFAQLELSRAGLEQELEAGVGGRFRCSCYGSAPMHGFAIWFQVTFPGGE
  SEKPLVLSTSPFHPATHWKQALLYLNEPVQVEQDTDVSGEITLLPSRDNPRRLRVLLRYK
  VGDQEEKTKDFAMED
• Function: Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA. Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates. Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a. H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3). Acts as a transcriptional repressor of various genes such as HOXA2, THBS1 and TP53. Repression of TP53 blocks cellular senescence. Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to the stimulation of its polymerase activity by enhancing DNA binding and processivity. Methylates HMGA1. Regulates alternative splicing events. Acts as a transcriptional coactivator of a number of steroid hormone receptors including ESR1, ESR2, PGR and NR3C1. Promotes fasting-induced transcriptional activation of the gluconeogenic program through methylation of the CRTC2 transcription coactivator. May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC). Methylates GPS2, protecting GPS2 from ubiquitination and degradation. Methylates SIRT7, inhibiting SIRT7 histone deacetylase activity and promoting mitochondria biogenesis.
• Tissue Specificity: Highly expressed in kidney and testis.
• Reactome Pathway:
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RMTs methylate histone arginines (R-HSA-3214858)
• BioCyc Pathway: MetaCyc:HS11391-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[5]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Lung neoplasm	DISVARNB	Strong	Biomarker	[7]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[11]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[12]
B-cell neoplasm	DISVY326	moderate	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[14]
Pulmonary emphysema	DIS5M7HZ	moderate	Altered Expression	[13]
Prostate cancer	DISF190Y	Disputed	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Colonic neoplasm	DISSZ04P	Limited	Biomarker	[9]
Kennedy disease	DISXZVM1	Limited	Genetic Variation	[17]

16 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 Protein arginine N-methyltransferase 6 (PRMT6).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[22]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[25]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[26]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[27]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin affects the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[32]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[33]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Protein arginine N-methyltransferase 6 (PRMT6).	[34]
(L-)-S-adenosyl-L-homocysteine	DMDUN83	Investigative	(L-)-S-adenosyl-L-homocysteine decreases the activity of Protein arginine N-methyltransferase 6 (PRMT6).	[35]

2 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 Protein arginine N-methyltransferase 6 (PRMT6).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein arginine N-methyltransferase 6 (PRMT6).	[28]

References

• [1] Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression.Carcinogenesis. 2019 Mar 12;40(1):15-26. doi: 10.1093/carcin/bgy147.
• [2] Thrombospondin-1 is a transcriptional repression target of PRMT6.J Biol Chem. 2009 Aug 7;284(32):21338-46. doi: 10.1074/jbc.M109.005322. Epub 2009 Jun 9.
• [3] PELP1 oncogenic functions involve alternative splicing via PRMT6.Mol Oncol. 2014 Mar;8(2):389-400. doi: 10.1016/j.molonc.2013.12.012. Epub 2013 Dec 30.
• [4] Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes.Endocr Relat Cancer. 2012 Jul 22;19(4):509-26. doi: 10.1530/ERC-12-0100. Print 2012 Aug.
• [5] A coupled fluorescence-based assay for the detection of protein arginine N-methyltransferase 6 (PRMT6) enzymatic activity.Anal Biochem. 2018 Apr 15;547:7-13. doi: 10.1016/j.ab.2018.01.023. Epub 2018 Feb 2.
• [6] Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9623-8. doi: 10.1073/pnas.1605045113. Epub 2016 Aug 9.
• [7] PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages.Mol Cancer Res. 2020 Jan;18(1):166-178. doi: 10.1158/1541-7786.MCR-19-0204. Epub 2019 Oct 16.
• [8] Protein arginine methyltransferase 6 suppresses adipogenic differentiation by repressing peroxisome proliferatoractivated receptor activity.Int J Mol Med. 2019 Jun;43(6):2462-2470. doi: 10.3892/ijmm.2019.4147. Epub 2019 Mar 27.
• [9] Intestinal PPAR Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6.Gastroenterology. 2019 Sep;157(3):744-759.e4. doi: 10.1053/j.gastro.2019.05.057. Epub 2019 May 30.
• [10] Arginine methylation of CRTC2 is critical in the transcriptional control of hepatic glucose metabolism.Sci Signal. 2014 Feb 25;7(314):ra19. doi: 10.1126/scisignal.2004479.
• [11] Evaluation of five candidate genes from GWAS for association with oligozoospermia in a Han Chinese population.PLoS One. 2013 Nov 26;8(11):e80374. doi: 10.1371/journal.pone.0080374. eCollection 2013.
• [12] p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6.Nucleic Acids Res. 2012 Oct;40(19):9534-42. doi: 10.1093/nar/gks858. Epub 2012 Sep 16.
• [13] The protective effect of PRMT6 overexpression on cigarette smoke extract-induced murine emphysema model.Int J Chron Obstruct Pulmon Dis. 2017 Nov 3;12:3245-3254. doi: 10.2147/COPD.S144881. eCollection 2017.
• [14] CRAF Methylation by PRMT6 Regulates Aerobic Glycolysis-Driven Hepatocarcinogenesis via ERK-Dependent PKM2 Nuclear Relocalization and Activation.Hepatology. 2020 Apr;71(4):1279-1296. doi: 10.1002/hep.30923. Epub 2020 Jan 24.
• [15] Histone methyltransferase PRMT6 plays an oncogenic role of in prostate cancer.Oncotarget. 2016 Aug 16;7(33):53018-53028. doi: 10.18632/oncotarget.10061.
• [16] PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation.Cell Rep. 2018 Oct 16;25(3):690-701.e8. doi: 10.1016/j.celrep.2018.09.053.
• [17] Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy.Neuron. 2015 Jan 7;85(1):88-100. doi: 10.1016/j.neuron.2014.12.031.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] 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.
• [24] Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9623-8. doi: 10.1073/pnas.1605045113. Epub 2016 Aug 9.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [28] 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.
• [29] 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.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [31] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [32] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [33] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [34] Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2. PLoS One. 2013 Apr 16;8(4):e61980. doi: 10.1371/journal.pone.0061980. Print 2013.
• [35] Ribavirin inhibits colorectal cancer growth by downregulating PRMT5 expression and H3R8me2s and H4R3me2s accumulation. Toxicol Appl Pharmacol. 2021 Mar 15;415:115450. doi: 10.1016/j.taap.2021.115450. Epub 2021 Feb 9.