Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3677ZG)

• DOT Name: Histone-lysine N-methyltransferase NSD3 (NSD3)
• Synonyms: EC 2.1.1.370; EC 2.1.1.371; Nuclear SET domain-containing protein 3; Protein whistle; WHSC1-like 1 isoform 9 with methyltransferase activity to lysine; Wolf-Hirschhorn syndrome candidate 1-like protein 1; WHSC1-like protein 1
• Gene Name: NSD3
• Related Disease:
  Advanced cancer
  Bladder cancer
  Carcinoma
  Childhood myelodysplastic syndrome
  Colorectal carcinoma
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Invasive ductal breast carcinoma
  Liver cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Nephrotic syndrome
  Non-small-cell lung cancer
  Pancreatic ductal carcinoma
  Plasma cell myeloma
  Schizophrenia
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Leukemia
  Adenocarcinoma
  Bone osteosarcoma
  Breast neoplasm
  leukaemia
  Lung cancer
  Lung neoplasm
  Neoplasm
  Osteosarcoma
  Overgrowth syndrome
  Pancreatic adenocarcinoma
  Small-cell lung cancer
• UniProt ID: NSD3_HUMAN
• PDB ID: 2DAQ; 2NCZ; 2ND1; 4GND; 4GNE; 4GNF; 4GNG; 4RXJ; 5UPD; 6CEN; 6G24; 6G25; 6G27; 6G29; 6G2B; 6G2C; 6G2E; 6G2F; 6G2O; 6G3P; 6G3T; 7CRP; 7CRQ; 7CRR; 7JYN
• EC Number: 2.1.1.370; 2.1.1.371
• Pfam ID: PF17907 ; PF17982 ; PF00855 ; PF00856
• Sequence:
  MDFSFSFMQGIMGNTIQQPPQLIDSANIRQEDAFDNNSDIAEDGGQTPYEATLQQGFQYP
  ATTEDLPPLTNGYPSSISVYETQTKYQSYNQYPNGSANGFGAVRNFSPTDYYHSEIPNTR
  PHEILEKPSPPQPPPPPSVPQTVIPKKTGSPEIKLKITKTIQNGRELFESSLCGDLLNEV
  QASEHTKSKHESRKEKRKKSNKHDSSRSEERKSHKIPKLEPEEQNRPNERVDTVSEKPRE
  EPVLKEEAPVQPILSSVPTTEVSTGVKFQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKI
  NTRGAREYHVQFFSNQPERAWVHEKRVREYKGHKQYEELLAEATKQASNHSEKQKIRKPR
  PQRERAQWDIGIAHAEKALKMTREERIEQYTFIYIDKQPEEALSQAKKSVASKTEVKKTR
  RPRSVLNTQPEQTNAGEVASSLSSTEIRRHSQRRHTSAEEEEPPPVKIAWKTAAARKSLP
  ASITMHKGSLDLQKCNMSPVVKIEQVFALQNATGDGKFIDQFVYSTKGIGNKTEISVRGQ
  DRLIISTPNQRNEKPTQSVSSPEATSGSTGSVEKKQQRRSIRTRSESEKSTEVVPKKKIK
  KEQVETVPQATVKTGLQKGASEISDSCKPLKKRSRASTDVEMTSSAYRDTSDSDSRGLSD
  LQVGFGKQVDSPSATADADVSDVQSMDSSLSRRGTGMSKKDTVCQICESSGDSLIPCEGE
  CCKHFHLECLGLASLPDSKFICMECKTGQHPCFSCKVSGKDVKRCSVGACGKFYHEACVR
  KFPTAIFESKGFRCPQHCCSACSMEKDIHKASKGRMMRCLRCPVAYHSGDACIAAGSMLV
  SSYILICSNHSKRSSNSSAVNVGFCFVCARGLIVQDHSDPMFSSYAYKSHYLLNESNRAE
  LMKLPMIPSSSASKKKCEKGGRLLCCESCPASFHPECLSIEMPEGCWNCNDCKAGKKLHY
  KQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYV
  EGDKSFAEGQTSINKTFKKALEEAAKRFQELKAQRESKEALEIEKNSRKPPPYKHIKANK
  VIGKVQIQVADLSEIPRCNCKPADENPCGLESECLNRMLQYECHPQVCPAGDRCQNQCFT
  KRLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFY
  MLTVTKDRIIDAGPKGNYSRFMNHSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFN
  YNLDCLGNGRTECHCGADNCSGFLGVRPKSACASTNEEKAKNAKLKQKRRKIKTEPKQMH
  EDYCFQCGDGGELVMCDKKDCPKAYHLLCLNLTQPPYGKWECPWHQCDECSSAAVSFCEF
  CPHSFCKDHEKGALVPSALEGRLCCSEHDPMAPVSPEYWSKIKCKWESQDHGEEVKE
• Function: Histone methyltransferase. Preferentially dimethylates 'Lys-4' and 'Lys-27' of histone H3 forming H3K2me2 and H3K27me2. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation, while 'Lys-27' is a mark for transcriptional repression.
• Tissue Specificity: Highly expressed in brain, heart and skeletal muscle. Expressed at lower level in liver and lung.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS07446-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Head and neck cancer	DISBPSQZ	Strong	Posttranslational Modification	[6]
Head and neck carcinoma	DISOU1DS	Strong	Posttranslational Modification	[6]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[6]
Invasive ductal breast carcinoma	DIS43J58	Strong	Biomarker	[7]
Liver cancer	DISDE4BI	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[4]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Biomarker	[10]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[12]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[13]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]
Leukemia	DISNAKFL	Disputed	Biomarker	[13]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[14]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[15]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[14]
leukaemia	DISS7D1V	Limited	Biomarker	[13]
Lung cancer	DISCM4YA	Limited	Biomarker	[8]
Lung neoplasm	DISVARNB	Limited	Biomarker	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[15]
Overgrowth syndrome	DISHK54G	Limited	Genetic Variation	[17]
Pancreatic adenocarcinoma	DISKHX7S	Limited	Biomarker	[14]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[14]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Histone-lysine N-methyltransferase NSD3 (NSD3).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Histone-lysine N-methyltransferase NSD3 (NSD3).	[28]

4 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 Histone-lysine N-methyltransferase NSD3 (NSD3).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Histone-lysine N-methyltransferase NSD3 (NSD3).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Histone-lysine N-methyltransferase NSD3 (NSD3).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Histone-lysine N-methyltransferase NSD3 (NSD3).	[27]

References

• [1] (1) H NMR metabolomics reveals increased glutaminolysis upon overexpression of NSD3s or Pdp3 in Saccharomyces cerevisiae.J Cell Biochem. 2019 Apr;120(4):5377-5385. doi: 10.1002/jcb.27816. Epub 2018 Oct 15.
• [2] The histone methyltransferase Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) is involved in human carcinogenesis.Genes Chromosomes Cancer. 2013 Feb;52(2):126-39. doi: 10.1002/gcc.22012. Epub 2012 Sep 25.
• [3] The NSD3L histone methyltransferase regulates cell cycle and cell invasion in breast cancer cells.Biochem Biophys Res Commun. 2010 Jul 30;398(3):565-70. doi: 10.1016/j.bbrc.2010.06.119. Epub 2010 Jul 1.
• [4] NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11;p15) and expression pattern of NSD family genes.Cancer Genet Cytogenet. 2009 Apr 15;190(2):108-12. doi: 10.1016/j.cancergencyto.2008.12.008.
• [5] Downregulation of NSD3 (WHSC1L1) inhibits cell proliferation and migration via ERK1/2 deactivation and decreasing CAPG expression in colorectal cancer cells.Onco Targets Ther. 2019 May 21;12:3933-3943. doi: 10.2147/OTT.S191732. eCollection 2019.
• [6] WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer.Sci Rep. 2017 Jan 19;7:40664. doi: 10.1038/srep40664.
• [7] Development of mammary hyperplasia, dysplasia, and invasive ductal carcinoma in transgenic mice expressing the 8p11 amplicon oncogene NSD3.Breast Cancer Res Treat. 2017 Jul;164(2):349-358. doi: 10.1007/s10549-017-4258-9. Epub 2017 May 8.
• [8] Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3.Nat Chem Biol. 2019 Aug;15(8):822-829. doi: 10.1038/s41589-019-0310-x. Epub 2019 Jul 8.
• [9] Wolf-Hirschhorn syndrome candidate 1-like 1 epigenetically regulates nephrin gene expression.Am J Physiol Renal Physiol. 2017 Jun 1;312(6):F1184-F1199. doi: 10.1152/ajprenal.00305.2016. Epub 2017 Feb 22.
• [10] High-resolution genomic profiles of human lung cancer.Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9625-30. doi: 10.1073/pnas.0504126102. Epub 2005 Jun 27.
• [11] NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis.Nat Cell Biol. 2007 Jul;9(7):804-12. doi: 10.1038/ncb1608. Epub 2007 Jun 24.
• [12] Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
• [13] NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler.Mol Cell. 2015 Dec 17;60(6):847-59. doi: 10.1016/j.molcel.2015.10.033. Epub 2015 Nov 25.
• [14] PPAPDC1B and WHSC1L1 are common drivers of the 8p11-12 amplicon, not only in breast tumors but also in pancreatic adenocarcinomas and lung tumors.Am J Pathol. 2013 Nov;183(5):1634-1644. doi: 10.1016/j.ajpath.2013.07.028. Epub 2013 Sep 17.
• [15] Silencing of histone methyltransferase NSD3 reduces cell viability in osteosarcoma with induction of apoptosis.Oncol Rep. 2017 Nov;38(5):2796-2802. doi: 10.3892/or.2017.5936. Epub 2017 Sep 4.
• [16] Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon.PLoS One. 2016 Feb 23;11(2):e0149628. doi: 10.1371/journal.pone.0149628. eCollection 2016.
• [17] Evaluation of NSD2 and NSD3 in overgrowth syndromes.Eur J Hum Genet. 2005 Feb;13(2):150-3. doi: 10.1038/sj.ejhg.5201298.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [20] 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.
• [21] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [22] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [24] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.