Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE5VET6)

• DOT Name: Histone-lysine N-trimethyltransferase SMYD5 (SMYD5)
• Synonyms: EC 2.1.1.372; Protein NN8-4AG; Retinoic acid-induced protein 15; SET and MYND domain-containing protein 5; -lysine20 N-trimethyltransferase SMYD5
• Gene Name: SMYD5
• Related Disease:
  Advanced cancer
  Chromosomal disorder
  Gastric cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Promyelocytic leukaemia
• UniProt ID: SMYD5_HUMAN
• EC Number: 2.1.1.372
• Pfam ID: PF00856
• Sequence:
  MAASMCDVFSFCVGVAGRARVSVEVRFVSSAKGKGLFATQLIRKGETIFVERPLVAAQFL
  WNALYRYRACDHCLRALEKAEENAQRLTGKPGQVLPHPELCTVRKDLHQNCPHCQVMYCS
  AECRLAATEQYHQVLCPGPSQDDPLHPLNKLQEAWRSIHYPPETASIMLMARMVATVKQA
  KDKDRWIRLFSQFCNKTANEEEEIVHKLLGDKFKGQLELLRRLFTEALYEEAVSQWFTPD
  GFRSLFALVGTNGQGIGTSSLSQWVHACDTLELKPQDREQLDAFIDQLYKDIEAATGEFL
  NCEGSGLFVLQSCCNHSCVPNAETSFPENNFLLHVTALEDIKPGEEICISYLDCCQRERS
  RHSRHKILRENYLFVCSCPKCLAEADEPNVTSEEEEEEEEEEEGEPEDAELGDEMTDV
• Function: Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4 to form trimethylated histone H4 lysine 20 (H4K20me3) which represents a specific tag for epigenetic transcriptional repression. In association with the NCoR corepressor complex, is involved in the repression of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages by catalyzing the formation of H4K20me3 at the gene promoters. Plays an important role in embryonic stem (ES) cell self-renewal and differentiation. Promotes ES cell maintenance by silencing differentiation genes through deposition of H4K20me3 marks. Maintains genome stability of ES cells during differentiation through regulation of heterochromatin formation and repression of endogenous repetitive DNA elements by depositing H4K20me3 marks.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Chromosomal disorder	DISM5BB5	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[2]
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
leukaemia	DISS7D1V	Strong	Altered Expression	[5]
Leukemia	DISNAKFL	Strong	Altered Expression	[5]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[6]

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-trimethyltransferase SMYD5 (SMYD5).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[11]

6 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-trimethyltransferase SMYD5 (SMYD5).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Histone-lysine N-trimethyltransferase SMYD5 (SMYD5).	[14]

References

• [1] SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation.Cancer Res. 2017 Dec 1;77(23):6729-6745. doi: 10.1158/0008-5472.CAN-17-0828. Epub 2017 Sep 26.
• [2] Comprehensive analysis of histone modification-associated genes on differential gene expression and prognosis in gastric cancer.Exp Ther Med. 2019 Sep;18(3):2219-2230. doi: 10.3892/etm.2019.7808. Epub 2019 Jul 24.
• [3] Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development.Development. 2002 Jun;129(11):2733-47. doi: 10.1242/dev.129.11.2733.
• [4] Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells.J Hepatol. 2013 Nov;59(5):1037-44. doi: 10.1016/j.jhep.2013.06.024. Epub 2013 Jul 2.
• [5] PML a target of translocations in APL is a regulator of cellular senescence.Leukemia. 2002 Oct;16(10):1918-26. doi: 10.1038/sj.leu.2402722.
• [6] Dual promoter usage as regulatory mechanism of let-7c expression in leukemic and solid tumors.Mol Cancer Res. 2014 Jun;12(6):878-89. doi: 10.1158/1541-7786.MCR-13-0410. Epub 2014 Mar 17.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.