Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBVVP9Q)

• DOT Name: Histone-lysine N-methyltransferase SETDB2 (SETDB2)
• Synonyms: EC 2.1.1.366; Chronic lymphocytic leukemia deletion region gene 8 protein; Lysine N-methyltransferase 1F; SET domain bifurcated 2
• Gene Name: SETDB2
• Related Disease:
  Acute leukaemia
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colorectal carcinoma
  Melanoma
  Neoplasm
  Non-insulin dependent diabetes
  Papillary renal cell carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Type-1/2 diabetes
• UniProt ID: SETB2_HUMAN
• PDB ID: 5TFP; 8HFP
• EC Number: 2.1.1.366
• Pfam ID: PF01429 ; PF05033 ; PF00856
• Sequence:
  MGEKNGDAKTFWMELEDDGKVDFIFEQVQNVLQSLKQKIKDGSATNKEYIQAMILVNEAT
  IINSSTSIKGASQKEVNAQSSDPMPVTQKEQENKSNAFPSTSCENSFPEDCTFLTTENKE
  ILSLEDKVVDFREKDSSSNLSYQSHDCSGACLMKMPLNLKGENPLQLPIKCHFQRRHAKT
  NSHSSALHVSYKTPCGRSLRNVEEVFRYLLETECNFLFTDNFSFNTYVQLARNYPKQKEV
  VSDVDISNGVESVPISFCNEIDSRKLPQFKYRKTVWPRAYNLTNFSSMFTDSCDCSEGCI
  DITKCACLQLTARNAKTSPLSSDKITTGYKYKRLQRQIPTGIYECSLLCKCNRQLCQNRV
  VQHGPQVRLQVFKTEQKGWGVRCLDDIDRGTFVCIYSGRLLSRANTEKSYGIDENGRDEN
  TMKNIFSKKRKLEVACSDCEVEVLPLGLETHPRTAKTEKCPPKFSNNPKELTVETKYDNI
  SRIQYHSVIRDPESKTAIFQHNGKKMEFVSSESVTPEDNDGFKPPREHLNSKTKGAQKDS
  SSNHVDEFEDNLLIESDVIDITKYREETPPRSRCNQATTLDNQNIKKAIEVQIQKPQEGR
  STACQRQQVFCDEELLSETKNTSSDSLTKFNKGNVFLLDATKEGNVGRFLNHSCCPNLLV
  QNVFVETHNRNFPLVAFFTNRYVKARTELTWDYGYEAGTVPEKEIFCQCGVNKCRKKIL
• Function: Histone methyltransferase involved in left-right axis specification in early development and mitosis. Specifically trimethylates 'Lys-9' of histone H3 (H3K9me3). H3K9me3 is a specific tag for epigenetic transcriptional repression that recruits HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Contributes to H3K9me3 in both the interspersed repetitive elements and centromere-associated repeats. Plays a role in chromosome condensation and segregation during mitosis.
• Tissue Specificity: Ubiquitous. Highest expression in heart, testis and ovary.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS06128-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Papillary renal cell carcinoma	DIS25HBV	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[2]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[6]
Type-1/2 diabetes	DISIUHAP	Disputed	Altered Expression	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[15]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[16]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Histone-lysine N-methyltransferase SETDB2 (SETDB2).	[20]

References

• [1] SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.Cell Rep. 2018 Apr 24;23(4):1166-1177. doi: 10.1016/j.celrep.2018.03.124.
• [2] 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.
• [3] Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability.Hum Pathol. 2014 Aug;45(8):1674-81. doi: 10.1016/j.humpath.2014.04.013. Epub 2014 Apr 24.
• [4] 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.
• [5] Diabetes Impedes the Epigenetic Switch of Macrophages into Repair Mode.Immunity. 2019 Aug 20;51(2):199-201. doi: 10.1016/j.immuni.2019.07.009.
• [6] Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia.Cancer Res. 2001 Apr 1;61(7):2870-7.
• [7] The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.Immunity. 2019 Aug 20;51(2):258-271.e5. doi: 10.1016/j.immuni.2019.06.015. Epub 2019 Jul 23.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] 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.
• [16] Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. doi: 10.1074/jbc.M112.432294. Epub 2013 Apr 1.
• [17] 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.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.