Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT49OXF)

• DOT Name: Histone-lysine N-methyltransferase SETD7 (SETD7)
• Synonyms: EC 2.1.1.364; Histone H3-K4 methyltransferase SETD7; H3-K4-HMTase SETD7; Lysine N-methyltransferase 7; SET domain-containing protein 7; SET7/9
• Gene Name: SETD7
• UniProt ID: SETD7_HUMAN
• PDB ID: 1H3I; 1MT6; 1MUF; 1N6A; 1N6C; 1O9S; 1XQH; 2F69; 3CBM; 3CBO; 3CBP; 3M53; 3M54; 3M55; 3M56; 3M57; 3M58; 3M59; 3M5A; 3OS5; 3VUZ; 3VV0; 4E47; 4J7F; 4J7I; 4J83; 4J8O; 4JDS; 4JLG; 5AYF; 5EG2; 5YLT
• EC Number: 2.1.1.364
• Pfam ID: PF02493 ; PF00856
• Sequence:
  MDSDDEMVEEAVEGHLDDDGLPHGFCTVTYSSTDRFEGNFVHGEKNGRGKFFFFDGSTLE
  GYYVDDALQGQGVYTYEDGGVLQGTYVDGELNGPAQEYDTDGRLIFKGQYKDNIRHGVCW
  IYYPDGGSLVGEVNEDGEMTGEKIAYVYPDERTALYGKFIDGEMIEGKLATLMSTEEGRP
  HFELMPGNSVYHFDKSTSSCISTNALLPDPYESERVYVAESLISSAGEGLFSKVAVGPNT
  VMSFYNGVRITHQEVDSRDWALNGNTLSLDEETVIDVPEPYNHVSKYCASLGHKANHSFT
  PNCIYDMFVHPRFGPIKCIRTLRAVEADEELTVAYGYDHSPPGKSGPEAPEWYQVELKAF
  QATQQK
• Function: Histone methyltransferase that specifically monomethylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Plays a central role in the transcriptional activation of genes such as collagenase or insulin. Recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription. Has also methyltransferase activity toward non-histone proteins such as CGAS, p53/TP53, TAF10, and possibly TAF7 by recognizing and binding the [KR]-[STA]-K in substrate proteins. Monomethylates 'Lys-189' of TAF10, leading to increase the affinity of TAF10 for RNA polymerase II. Monomethylates 'Lys-372' of p53/TP53, stabilizing p53/TP53 and increasing p53/TP53-mediated transcriptional activation. Monomethylates 'Lys-491' of CGAS, promoting interaction between SGF29 and CGAS.
• Tissue Specificity: Widely expressed. Expressed in pancreatic islets.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  FoxO sig.ling pathway (hsa04068)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS07252-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Histone-lysine N-methyltransferase SETD7 (SETD7) increases the response to substance of Doxorubicin.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone-lysine N-methyltransferase SETD7 (SETD7).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Histone-lysine N-methyltransferase SETD7 (SETD7).	[11]

12 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 SETD7 (SETD7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[7]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Histone-lysine N-methyltransferase SETD7 (SETD7).	[14]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [8] 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.
• [9] 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.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] 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.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] KMT Set7/9 affects genotoxic stress response via the Mdm2 axis. Oncotarget. 2015 Sep 22;6(28):25843-55. doi: 10.18632/oncotarget.4584.