Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO5RAU2)

• DOT Name: Actin-histidine N-methyltransferase (SETD3)
• Synonyms: EC 2.1.1.85; Protein-L-histidine N-tele-methyltransferase; SET domain-containing protein 3; hSETD3
• Gene Name: SETD3
• Related Disease:
  Hepatocellular carcinoma
  Adult lymphoma
  B-cell neoplasm
  Clear cell renal carcinoma
  High blood pressure
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Pulmonary arterial hypertension
  Enterovirus infection
  Epidermodysplasia verruciformis
  Nervous system disease
  Viral encephalitis
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: SETD3_HUMAN
• PDB ID: 3SMT; 6ICT; 6ICV; 6JAT; 6MBJ; 6MBK; 6MBL; 6OX0; 6OX1; 6OX2; 6OX3; 6OX4; 6OX5; 6V62; 6V63; 6WK1; 6WK2; 7LMS; 7W28; 7W29
• EC Number: 2.1.1.85
• Pfam ID: PF09273 ; PF00856
• Sequence:
  MGKKSRVKTQKSGTGATATVSPKEILNLTSELLQKCSSPAPGPGKEWEEYVQIRTLVEKI
  RKKQKGLSVTFDGKREDYFPDLMKWASENGASVEGFEMVNFKEEGFGLRATRDIKAEELF
  LWVPRKLLMTVESAKNSVLGPLYSQDRILQAMGNIALAFHLLCERASPNSFWQPYIQTLP
  SEYDTPLYFEEDEVRYLQSTQAIHDVFSQYKNTARQYAYFYKVIQTHPHANKLPLKDSFT
  YEDYRWAVSSVMTRQNQIPTEDGSRVTLALIPLWDMCNHTNGLITTGYNLEDDRCECVAL
  QDFRAGEQIYIFYGTRSNAEFVIHSGFFFDNNSHDRVKIKLGVSKSDRLYAMKAEVLARA
  GIPTSSVFALHFTEPPISAQLLAFLRVFCMTEEELKEHLLGDSAIDRIFTLGNSEFPVSW
  DNEVKLWTFLEDRASLLLKTYKTTIEEDKSVLKNHDLSVRAKMAIKLRLGEKEILEKAVK
  SAAVNREYYRQQMEEKAPLPKYEESNLGLLESSVGDSRLPLVLRNLEEEAGVQDALNIRE
  AISKAKATENGLVNGENSIPNGTRSENESLNQESKRAVEDAKGSSSDSTAGVKE
• Function: Protein-histidine N-methyltransferase that specifically mediates 3-methylhistidine (tele-methylhistidine) methylation of actin at 'His-73'. Histidine methylation of actin is required for smooth muscle contraction of the laboring uterus during delivery. Does not have protein-lysine N-methyltransferase activity and probably only catalyzes histidine methylation of actin.
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Lymphoma	DISN6V4S	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[2]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[6]
Enterovirus infection	DISH2UDP	moderate	Biomarker	[7]
Epidermodysplasia verruciformis	DIS54WBS	moderate	Biomarker	[7]
Nervous system disease	DISJ7GGT	moderate	Biomarker	[7]
Viral encephalitis	DIS9G09S	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[5]
Liver cancer	DISDE4BI	Limited	Altered Expression	[5]

3 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 Actin-histidine N-methyltransferase (SETD3).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Actin-histidine N-methyltransferase (SETD3).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Actin-histidine N-methyltransferase (SETD3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Actin-histidine N-methyltransferase (SETD3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Actin-histidine N-methyltransferase (SETD3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Actin-histidine N-methyltransferase (SETD3).	[11]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Actin-histidine N-methyltransferase (SETD3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Actin-histidine N-methyltransferase (SETD3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Actin-histidine N-methyltransferase (SETD3).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Actin-histidine N-methyltransferase (SETD3).	[17]

References

• [1] SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma.Clin Sci (Lond). 2019 Oct 30;133(20):2085-2105. doi: 10.1042/CS20190666.
• [2] The role of a newly identified SET domain-containing protein, SETD3, in oncogenesis.Haematologica. 2013 May;98(5):739-43. doi: 10.3324/haematol.2012.066977. Epub 2012 Oct 12.
• [3] SETDB2 and RIOX2 are differentially expressed among renal cell tumor subtypes, associating with prognosis and metastization.Epigenetics. 2017;12(12):1057-1064. doi: 10.1080/15592294.2017.1385685. Epub 2018 Jan 22.
• [4] Structural insights into SETD3-mediated histidine methylation on -actin.Elife. 2019 Feb 20;8:e43676. doi: 10.7554/eLife.43676.
• [5] Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis.J Biol Chem. 2017 Jun 2;292(22):9022-9033. doi: 10.1074/jbc.M117.778001. Epub 2017 Apr 25.
• [6] Forkhead box M1 transcription factor: a novel target for pulmonary arterial hypertension therapy.World J Pediatr. 2020 Apr;16(2):113-119. doi: 10.1007/s12519-019-00271-1. Epub 2019 Jun 12.
• [7] Enterovirus pathogenesis requires the host methyltransferase SETD3.Nat Microbiol. 2019 Dec;4(12):2523-2537. doi: 10.1038/s41564-019-0551-1. Epub 2019 Sep 16.
• [8] 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.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] 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.
• [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.
• [15] 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.
• [16] 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.
• [17] 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.