Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH5APN1)

• DOT Name: N-lysine methyltransferase SETD6 (SETD6)
• Synonyms: EC 2.1.1.-; SET domain-containing protein 6
• Gene Name: SETD6
• Related Disease:
  Advanced cancer
  Familial colorectal cancer type X
  Bladder cancer
  Breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
  Colorectal cancer
• UniProt ID: SETD6_HUMAN
• PDB ID: 3QXY; 3RC0
• EC Number: 2.1.1.-
• Pfam ID: PF09273 ; PF00856
• Sequence:
  MATQAKRPRVAGPVDGGDLDPVACFLSWCRRVGLELSPKVSERAGGRRTRGGARAALTSP
  PAQVAVSRQGTVAGYGMVARESVQAGELLFVVPRAALLSQHTCSIGGLLERERVALQSQS
  GWVPLLLALLHELQAPASRWRPYFALWPELGRLEHPMFWPEEERRCLLQGTGVPEAVEKD
  LANIRSEYQSIVLPFMEAHPDLFSLRVRSLELYHQLVALVMAYSFQEPLEEEEDEKEPNS
  PVMVPAADILNHLANHNANLEYSANCLRMVATQPIPKGHEIFNTYGQMANWQLIHMYGFV
  EPYPDNTDDTADIQMVTVREAALQGTKTEAERHLVYERWDFLCKLEMVGEEGAFVIGREE
  VLTEEELTTTLKVLCMPAEEFRELKDQDGGGDDKREEGSLTITNIPKLKASWRQLLQNSV
  LLTLQTYATDLKTDQGLLSNKEVYAKLSWREQQALQVRYGQKMILHQLLELTS
• Function: Protein-lysine N-methyltransferase. Monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity. Monomethylates 'Lys-8' of H2AZ (H2AZK8me1). Required for the maintenance of embryonic stem cell self-renewal. Methylates PAK4.
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Familial colorectal cancer type X	DISEBNIA	Definitive	Genetic Variation	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Limited	Posttranslational Modification	[3]
Colorectal cancer	DISNH7P9	Limited	Unknown	[4]

12 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 N-lysine methyltransferase SETD6 (SETD6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-lysine methyltransferase SETD6 (SETD6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-lysine methyltransferase SETD6 (SETD6).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-lysine methyltransferase SETD6 (SETD6).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of N-lysine methyltransferase SETD6 (SETD6).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of N-lysine methyltransferase SETD6 (SETD6).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of N-lysine methyltransferase SETD6 (SETD6).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of N-lysine methyltransferase SETD6 (SETD6).	[12]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of N-lysine methyltransferase SETD6 (SETD6).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of N-lysine methyltransferase SETD6 (SETD6).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N-lysine methyltransferase SETD6 (SETD6).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-lysine methyltransferase SETD6 (SETD6).	[7]

References

• [1] SETD6 dominant negative mutation in familial colorectal cancer type X.Hum Mol Genet. 2017 Nov 15;26(22):4481-4493. doi: 10.1093/hmg/ddx336.
• [2] SETD6 regulates NF-B signaling in urothelial cell survival: Implications for bladder cancer.Oncotarget. 2017 Feb 28;8(9):15114-15125. doi: 10.18632/oncotarget.14750.
• [3] Lysines 207 and 325 methylation of WDR5 catalyzed by SETD6 promotes breast cancer cell proliferation and migration.Oncol Rep. 2018 Nov;40(5):3069-3077. doi: 10.3892/or.2018.6669. Epub 2018 Aug 23.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] 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.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] 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.
• [14] 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.