Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWVUA1B)

• DOT Name: Histone-lysine N-methyltransferase SETDB1 (SETDB1)
• Synonyms: EC 2.1.1.366; ERG-associated protein with SET domain; ESET; Histone H3-K9 methyltransferase 4; H3-K9-HMTase 4; Lysine N-methyltransferase 1E; SET domain bifurcated 1
• Gene Name: SETDB1
• Related Disease:
  Adenoma
  Advanced cancer
  Autism
  Benign prostatic hyperplasia
  Breast neoplasm
  Carcinoma
  Cockayne syndrome type 2
  Colorectal carcinoma
  Epithelial ovarian cancer
  Haematological malignancy
  Head and neck cancer
  Head and neck carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Huntington disease
  Influenza
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Malignant pleural mesothelioma
  Melanoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prader-Willi syndrome
  Prostate neoplasm
  Schizophrenia
  Autism spectrum disorder
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Small-cell lung cancer
  Breast cancer
  Breast carcinoma
  Colon adenocarcinoma
  Congenital contractural arachnodactyly
  Mesothelioma
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SETB1_HUMAN
• PDB ID: 3DLM; 4X3S; 5KCH; 5KCO; 5KE2; 5KE3; 5KH6; 5QT1; 5QT2; 6AU2; 6AU3; 6BHD; 6BHE; 6BHG; 6BHH; 6BHI; 6BPI; 7C9N; 7CAJ; 7CD9; 7CJT; 8G5E; 8UWP
• EC Number: 2.1.1.366
• Pfam ID: PF18300 ; PF01429 ; PF05033 ; PF00856 ; PF18358 ; PF18359
• Sequence:
  MSSLPGCIGLDAATATVESEEIAELQQAVVEELGISMEELRHFIDEELEKMDCVQQRKKQ
  LAELETWVIQKESEVAHVDQLFDDASRAVTNCESLVKDFYSKLGLQYRDSSSEDESSRPT
  EIIEIPDEDDDVLSIDSGDAGSRTPKDQKLREAMAALRKSAQDVQKFMDAVNKKSSSQDL
  HKGTLSQMSGELSKDGDLIVSMRILGKKRTKTWHKGTLIAIQTVGPGKKYKVKFDNKGKS
  LLSGNHIAYDYHPPADKLYVGSRVVAKYKDGNQVWLYAGIVAETPNVKNKLRFLIFFDDG
  YASYVTQSELYPICRPLKKTWEDIEDISCRDFIEEYVTAYPNRPMVLLKSGQLIKTEWEG
  TWWKSRVEEVDGSLVRILFLDDKRCEWIYRGSTRLEPMFSMKTSSASALEKKQGQLRTRP
  NMGAVRSKGPVVQYTQDLTGTGTQFKPVEPPQPTAPPAPPFPPAPPLSPQAGDSDLESQL
  AQSRKQVAKKSTSFRPGSVGSGHSSPTSPALSENVSGGKPGINQTYRSPLGSTASAPAPS
  ALPAPPAPPVFHGMLERAPAEPSYRAPMEKLFYLPHVCSYTCLSRVRPMRNEQYRGKNPL
  LVPLLYDFRRMTARRRVNRKMGFHVIYKTPCGLCLRTMQEIERYLFETGCDFLFLEMFCL
  DPYVLVDRKFQPYKPFYYILDITYGKEDVPLSCVNEIDTTPPPQVAYSKERIPGKGVFIN
  TGPEFLVGCDCKDGCRDKSKCACHQLTIQATACTPGGQINPNSGYQYKRLEECLPTGVYE
  CNKRCKCDPNMCTNRLVQHGLQVRLQLFKTQNKGWGIRCLDDIAKGSFVCIYAGKILTDD
  FADKEGLEMGDEYFANLDHIESVENFKEGYESDAPCSSDSSGVDLKDQEDGNSGTEDPEE
  SNDDSSDDNFCKDEDFSTSSVWRSYATRRQTRGQKENGLSETTSKDSHPPDLGPPHIPVP
  PSIPVGGCNPPSSEETPKNKVASWLSCNSVSEGGFADSDSHSSFKTNEGGEGRAGGSRME
  AEKASTSGLGIKDEGDIKQAKKEDTDDRNKMSVVTESSRNYGYNPSPVKPEGLRRPPSKT
  SMHQSRRLMASAQSNPDDVLTLSSSTESEGESGTSRKPTAGQTSATAVDSDDIQTISSGS
  EGDDFEDKKNMTGPMKRQVAVKSTRGFALKSTHGIAIKSTNMASVDKGESAPVRKNTRQF
  YDGEESCYIIDAKLEGNLGRYLNHSCSPNLFVQNVFVDTHDLRFPWVAFFASKRIRAGTE
  LTWDYNYEVGSVEGKELLCCCGAIECRGRLL
• Function: Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation. Required for HUSH-mediated heterochromatin formation and gene silencing. Forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells. Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). In ESCs, in collaboration with TRIM28, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway. Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions.
• Tissue Specificity: Widely expressed. High expression in testis.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS07042-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Cockayne syndrome type 2	DIS3X0GQ	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[7]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[8]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[9]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[9]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Huntington disease	DISQPLA4	Strong	Biomarker	[12]
Influenza	DIS3PNU3	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[15]
Malignant pleural mesothelioma	DIST2R60	Strong	Genetic Variation	[16]
Melanoma	DIS1RRCY	Strong	Biomarker	[17]
Neoplasm	DISZKGEW	Strong	Biomarker	[18]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Prader-Willi syndrome	DISYWMLU	Strong	Altered Expression	[19]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[20]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[21]
Autism spectrum disorder	DISXK8NV	moderate	Biomarker	[22]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[22]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[18]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[23]
Breast cancer	DIS7DPX1	Limited	Biomarker	[24]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[24]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[25]
Congenital contractural arachnodactyly	DISOM1K7	Limited	Biomarker	[26]
Mesothelioma	DISKWK9M	Limited	Genetic Variation	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[27]
Prostate cancer	DISF190Y	Limited	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[28]

5 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 Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[30]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[34]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the methylation of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[31]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone-lysine N-methyltransferase SETDB1 (SETDB1).	[35]

References

• [1] Notch1 counteracts WNT/-catenin signaling through chromatin modification in colorectal cancer.J Clin Invest. 2012 Sep;122(9):3248-59. doi: 10.1172/JCI61216. Epub 2012 Aug 6.
• [2] Histone methyltransferase SETDB1 promotes colorectal cancer proliferation through the STAT1-CCND1/CDK6 axis.Carcinogenesis. 2020 Jul 10;41(5):678-688. doi: 10.1093/carcin/bgz131.
• [3] The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.Autism Res. 2012 Dec;5(6):385-97. doi: 10.1002/aur.1251. Epub 2012 Oct 10.
• [4] Histone methyltransferase SETDB1 is required for prostate cancer cell proliferation, migration and invasion.Asian J Androl. 2014 Mar-Apr;16(2):319-24. doi: 10.4103/1008-682X.122812.
• [5] Setdb1, a novel interactor of Np63, is involved in breast tumorigenesis.Oncotarget. 2016 May 17;7(20):28836-48. doi: 10.18632/oncotarget.7089.
• [6] Cockayne syndrome group B deficiency reduces H3K9me3 chromatin remodeler SETDB1 and exacerbates cellular aging.Nucleic Acids Res. 2019 Sep 19;47(16):8548-8562. doi: 10.1093/nar/gkz568.
• [7] Serum circSETDB1 is a promising biomarker for predicting response to platinum-taxane-combined chemotherapy and relapse in high-grade serous ovarian cancer.Onco Targets Ther. 2019 Sep 11;12:7451-7457. doi: 10.2147/OTT.S220700. eCollection 2019.
• [8] SETDB1 modulates the differentiation of both the crystal cells and the lamellocytes in Drosophila.Dev Biol. 2019 Dec 1;456(1):74-85. doi: 10.1016/j.ydbio.2019.08.008. Epub 2019 Aug 15.
• [9] Knockdown of SET Domain, Bifurcated 1 suppresses head and neck cancer cell viability and wound-healing ability in vitro.Turk J Biol. 2019 Oct 14;43(5):281-292. doi: 10.3906/biy-1903-71. eCollection 2019.
• [10] HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase.J Hepatol. 2015 Nov;63(5):1093-102. doi: 10.1016/j.jhep.2015.06.023. Epub 2015 Jul 2.
• [11] MicroRNA-621 Acts as a Tumor Radiosensitizer by Directly Targeting SETDB1 in Hepatocellular Carcinoma.Mol Ther. 2019 Feb 6;27(2):355-364. doi: 10.1016/j.ymthe.2018.11.005. Epub 2018 Nov 13.
• [12] Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations.Hum Mol Genet. 2018 Dec 1;27(23):4117-4134. doi: 10.1093/hmg/ddy304.
• [13] Transcriptional derepression of the ERVWE1 locus following influenza A virus infection.J Virol. 2014 Apr;88(8):4328-37. doi: 10.1128/JVI.03628-13. Epub 2014 Jan 29.
• [14] H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis.Cancer Res. 2014 Dec 15;74(24):7333-43. doi: 10.1158/0008-5472.CAN-13-3572. Epub 2014 Dec 4.
• [15] Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016 Apr;48(4):407-16. doi: 10.1038/ng.3520. Epub 2016 Feb 29.
• [16] Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.Oncotarget. 2016 Feb 16;7(7):8321-31. doi: 10.18632/oncotarget.7032.
• [17] Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming.Clin Epigenetics. 2019 Mar 8;11(1):43. doi: 10.1186/s13148-019-0644-y.
• [18] SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis.Nat Cell Biol. 2019 Feb;21(2):214-225. doi: 10.1038/s41556-018-0266-1. Epub 2019 Jan 28.
• [19] Epigenetic therapy of Prader-Willi syndrome.Transl Res. 2019 Jun;208:105-118. doi: 10.1016/j.trsl.2019.02.012. Epub 2019 Mar 5.
• [20] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [21] The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain.Nat Genet. 2017 Aug;49(8):1239-1250. doi: 10.1038/ng.3906. Epub 2017 Jul 3.
• [22] Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.Pediatr Res. 2016 Sep;80(3):371-81. doi: 10.1038/pr.2016.101. Epub 2016 Apr 27.
• [23] Identification and characterization of the first fragment hits for SETDB1 Tudor domain.Bioorg Med Chem. 2019 Sep 1;27(17):3866-3878. doi: 10.1016/j.bmc.2019.07.020. Epub 2019 Jul 12.
• [24] SETDB1 induces epithelialmesenchymal transition in breast carcinoma by directly binding with Snail promoter.Oncol Rep. 2019 Feb;41(2):1284-1292. doi: 10.3892/or.2018.6871. Epub 2018 Nov 19.
• [25] Significance of histone methyltransferase SETDB1 expression in colon adenocarcinoma.APMIS. 2017 Nov;125(11):985-995. doi: 10.1111/apm.12745. Epub 2017 Sep 15.
• [26] LncRNA FENDRR represses proliferation, migration and invasion through suppression of survivin in cholangiocarcinoma cells.Cell Cycle. 2019 Apr;18(8):889-897. doi: 10.1080/15384101.2019.1598726. Epub 2019 Apr 14.
• [27] Enhanced expression of SETDB1 possesses prognostic value and promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma.Oncol Rep. 2018 Aug;40(2):1017-1025. doi: 10.3892/or.2018.6490. Epub 2018 Jun 14.
• [28] Quantitative proteomic study of human prostate cancer cells with different metastatic potentials.Int J Oncol. 2016 Apr;48(4):1437-46. doi: 10.3892/ijo.2016.3378. Epub 2016 Feb 4.
• [29] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [30] 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.
• [31] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [32] 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.
• [33] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [34] 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.
• [35] 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.
• [36] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.