Details of Drug Off-Target (DOT)

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

• DOT Name: Inactive histone-lysine N-methyltransferase 2E (KMT2E)
• Synonyms: Inactive lysine N-methyltransferase 2E; Myeloid/lymphoid or mixed-lineage leukemia protein 5
• Gene Name: KMT2E
• Related Disease:
  Cervical cancer
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 40
  Adenocarcinoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Autism
  Chromosomal disorder
  HIV infectious disease
  Intellectual disability
  Neoplasm
  Neurodevelopmental disorder
  O'Donnell-Luria-Rodan syndrome
  Myeloid leukaemia
  Syndromic intellectual disability
  Acute myelogenous leukaemia
  Glioblastoma multiforme
  Leukemia
• UniProt ID: KMT2E_HUMAN
• PDB ID: 2LV9; 4L58; 5HT6
• Pfam ID: PF20826 ; PF00856
• Sequence:
  MSIVIPLGVDTAETSYLEMAAGSEPESVEASPVVVEKSNSYPHQLYTSSSHHSHSYIGLP
  YADHNYGARPPPTPPASPPPSVLISKNEVGIFTTPNFDETSSATTISTSEDGSYGTDVTR
  CICGFTHDDGYMICCDKCSVWQHIDCMGIDRQHIPDTYLCERCQPRNLDKERAVLLQRRK
  RENMSDGDTSATESGDEVPVELYTAFQHTPTSITLTASRVSKVNDKRRKKSGEKEQHISK
  CKKAFREGSRKSSRVKGSAPEIDPSSDGSNFGWETKIKAWMDRYEEANNNQYSEGVQREA
  QRIALRLGNGNDKKEMNKSDLNTNNLLFKPPVESHIQKNKKILKSAKDLPPDALIIEYRG
  KFMLREQFEANGYFFKRPYPFVLFYSKFHGLEMCVDARTFGNEARFIRRSCTPNAEVRHE
  IQDGTIHLYIYSIHSIPKGTEITIAFDFDYGNCKYKVDCACLKENPECPVLKRSSESMEN
  INSGYETRRKKGKKDKDISKEKDTQNQNITLDCEGTTNKMKSPETKQRKLSPLRLSVSNN
  QEPDFIDDIEEKTPISNEVEMESEEQIAERKRKMTREERKMEAILQAFARLEKREKRREQ
  ALERISTAKTEVKTECKDTQIVSDAEVIQEQAKEENASKPTPAKVNRTKQRKSFSRSRTH
  IGQQRRRHRTVSMCSDIQPSSPDIEVTSQQNDIENTVLTIEPETETALAEIITETEVPAL
  NKCPTKYPKTKKHLVNEWLSEKNEKTGKPSDGLSERPLRITTDPEVLATQLNSLPGLTYS
  PHVYSTPKHYIRFTSPFLSEKRRRKEPTENISGSCKKRWLKQALEEENSAILHRFNSPCQ
  ERSRSPAVNGENKSPLLLNDSCSLPDLTTPLKKRRFYQLLDSVYSETSTPTPSPYATPTH
  TDITPMDPSFATPPRIKSDDETCRNGYKPIYSPVTPVTPGTPGNTMHFENISSPESSPEI
  KRRTYSQEGYDRSSTMLTLGPFRNSNLTELGLQEIKTIGYTSPRSRTEVNRQCPGEKEPV
  SDLQLGLDAVEPTALHKTLETPAHDRAEPNSQLDSTHSGRGTMYSSWVKSPDRTGVNFSV
  NSNLRDLTPSHQLEVGGGFRISESKCLMQDDTRGMFMETTVFCTSEDGLVSGFGRTVNDN
  LIDGNCTPQNPPQKKKVSLLEYRKRQREARKSGSKTENFPLISVSPHASGSLSNNGDGCA
  SSNDNGEQVDHTASLPLPTPATVYNATSEETSNNCPVKDATASEKNEPEVQWTASTSVEQ
  VRERSYQRALLLSDHRKDKDSGGESPCVSCSPSHVQSSPSSHSNHIPQLQAKGPVPSFSE
  LMEDPDPENPEPTTTNECPSPDTSQNTCKSPPKMSKPGSPGSVIPAQAHGKIFTKPDPQW
  DSTVSASEAENGVHLKTELQQKQLSNNNQALSKNHPPQTHVRNSSEQLSQKLPSVPTKLH
  CPPSPHLENPPKSSTPHTPVQHGYLSPKPPSQQLGSPYRPHHSQSPQVGTPQREPQRNFY
  PAAQNLPANTQQATSGTLFTQTPSGQSSATYSQFNQQSLNSTAPPPPPPPPPSSSYYQNQ
  QPSANFQNYNQLKGSLSQQTVFTSGPNQALPGTTSQQTVPGHHVTPGHFLPSQNPTIHHQ
  TAAAVVPPPPPPPPAPGPHLVQQPNSHQQHSVAHVVGPVHAVTPGSHIHSQTAGHHLPPP
  PPPPGPAPHHHPPPHPSTGLQGLQAQHQHVVNSAPPPPPPPPPSSVLASGHHTTSAQALH
  HPPHQGPPLFPSSAHPTVPPYPSQATHHTTLGPGPQHQPSGTGPHCPLPVTGPHLQPQGP
  NSIPTPTASGFCPHPGSVALPHGVQGPQQASPVPGQIPIHRAQVPPTFQNNYHGSGWH
• Function: Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription. Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation. Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry. Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition. During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells; [Isoform NKp44L]: Cellular ligand for NCR2/NKp44, may play a role as a danger signal in cytotoxicity and NK-cell-mediated innate immunity.
• Tissue Specificity: Widely expressed in both adult and fetal tissues . Highest levels of expression observed in fetal thymus and kidney and in adult hematopoietic tissues, jejunum and cerebellum . Isoform NKp44L: Not detected on circulating cells from healthy individuals, but is expressed on a large panel of tumor and transformed cells .
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS00145-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[3]
O'Donnell-Luria-Rodan syndrome	DISY25CS	Strong	Autosomal dominant	[3]
Myeloid leukaemia	DISMN944	moderate	Biomarker	[10]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Posttranslational Modification	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[5]
Leukemia	DISNAKFL	Limited	Altered Expression	[12]

11 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 Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[18]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Inactive histone-lysine N-methyltransferase 2E (KMT2E).	[17]

References

• [1] A novel MLL5 isoform that is essential to activate E6 and E7 transcription in HPV16/18-associated cervical cancers.Cancer Res. 2011 Nov 1;71(21):6696-707. doi: 10.1158/0008-5472.CAN-11-1271. Epub 2011 Sep 9.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy. Am J Hum Genet. 2019 Jun 6;104(6):1210-1222. doi: 10.1016/j.ajhg.2019.03.021. Epub 2019 May 9.
• [4] Mixed Lineage Leukemia 5 (MLL5) Protein Stability Is Cooperatively Regulated by O-GlcNac Transferase (OGT) and Ubiquitin Specific Protease 7 (USP7).PLoS One. 2015 Dec 17;10(12):e0145023. doi: 10.1371/journal.pone.0145023. eCollection 2015.
• [5] MLL5 Orchestrates a Cancer Self-Renewal State by Repressing the Histone Variant H3.3 and Globally Reorganizing Chromatin.Cancer Cell. 2015 Dec 14;28(6):715-729. doi: 10.1016/j.ccell.2015.10.005. Epub 2015 Nov 25.
• [6] Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.PLoS Genet. 2014 Feb 27;10(2):e1004201. doi: 10.1371/journal.pgen.1004201. eCollection 2014 Feb.
• [7] MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression.Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):757-62. doi: 10.1073/pnas.2036345100. Epub 2004 Jan 12.
• [8] NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand.Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10981-6. doi: 10.1073/pnas.0504315102. Epub 2005 Jul 26.
• [9] NKp44-NKp44 Ligand Interactions in the Regulation of Natural Killer Cells and Other Innate Lymphoid Cells in Humans.Front Immunol. 2019 Apr 9;10:719. doi: 10.3389/fimmu.2019.00719. eCollection 2019.
• [10] Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation.Blood. 2009 Feb 12;113(7):1432-43. doi: 10.1182/blood-2008-06-162263. Epub 2008 Oct 14.
• [11] Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia.Haematologica. 2014 Sep;99(9):1456-64. doi: 10.3324/haematol.2013.101386. Epub 2014 Jun 3.
• [12] Prognostic importance of histone methyltransferase MLL5 expression in acute myeloid leukemia.J Clin Oncol. 2011 Feb 20;29(6):682-9. doi: 10.1200/JCO.2010.31.1118. Epub 2011 Jan 4.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [19] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.