Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNNSM9P)

• DOT Name: Lysine-specific demethylase 2A (KDM2A)
• Synonyms: EC 1.14.11.27; CXXC-type zinc finger protein 8; F-box and leucine-rich repeat protein 11; F-box protein FBL7; F-box protein Lilina; F-box/LRR-repeat protein 11; JmjC domain-containing histone demethylation protein 1A; -lysine-36 demethylase 1A
• Gene Name: KDM2A
• UniProt ID: KDM2A_HUMAN
• PDB ID: 2YU1; 2YU2; 4BBQ; 6BYH; 6C16; 7UV9
• EC Number: 1.14.11.27
• Pfam ID: PF12937 ; PF17811 ; PF16866 ; PF02008
• Sequence:
  MEPEEERIRYSQRLRGTMRRRYEDDGISDDEIEGKRTFDLEEKLHTNKYNANFVTFMEGK
  DFNVEYIQRGGLRDPLIFKNSDGLGIKMPDPDFTVNDVKMCVGSRRMVDVMDVNTQKGIE
  MTMAQWTRYYETPEEEREKLYNVISLEFSHTRLENMVQRPSTVDFIDWVDNMWPRHLKES
  QTESTNAILEMQYPKVQKYCLMSVRGCYTDFHVDFGGTSVWYHIHQGGKVFWLIPPTAHN
  LELYENWLLSGKQGDIFLGDRVSDCQRIELKQGYTFVIPSGWIHAVYTPTDTLVFGGNFL
  HSFNIPMQLKIYNIEDRTRVPNKFRYPFYYEMCWYVLERYVYCITNRSHLTKEFQKESLS
  MDLELNGLESGNGDEEAVDREPRRLSSRRSVLTSPVANGVNLDYDGLGKTCRSLPSLKKT
  LAGDSSSDCSRGSHNGQVWDPQCAPRKDRQVHLTHFELEGLRCLVDKLESLPLHKKCVPT
  GIEDEDALIADVKILLEELANSDPKLALTGVPIVQWPKRDKLKFPTRPKVRVPTIPITKP
  HTMKPAPRLTPVRPAAASPIVSGARRRRVRCRKCKACVQGECGVCHYCRDMKKFGGPGRM
  KQSCVLRQCLAPRLPHSVTCSLCGEVDQNEETQDFEKKLMECCICNEIVHPGCLQMDGEG
  LLNEELPNCWECPKCYQEDSSEKAQKRKMEESDEEAVQAKVLRPLRSCDEPLTPPPHSPT
  SMLQLIHDPVSPRGMVTRSSPGAGPSDHHSASRDERFKRRQLLRLQATERTMVREKENNP
  SGKKELSEVEKAKIRGSYLTVTLQRPTKELHGTSIVPKLQAITASSANLRHSPRVLVQHC
  PARTPQRGDEEGLGGEEEEEEEEEEEDDSAEEGGAARLNGRGSWAQDGDESWMQREVWMS
  VFRYLSRRELCECMRVCKTWYKWCCDKRLWTKIDLSRCKAIVPQALSGIIKRQPVSLDLS
  WTNISKKQLTWLVNRLPGLKDLLLAGCSWSAVSALSTSSCPLLRTLDLRWAVGIKDPQIR
  DLLTPPADKPGQDNRSKLRNMTDFRLAGLDITDATLRLIIRHMPLLSRLDLSHCSHLTDQ
  SSNLLTAVGSSTRYSLTELNMAGCNKLTDQTLIYLRRIANVTLIDLRGCKQITRKACEHF
  ISDLSINSLYCLSDEKLIQKIS
• Function: Histone demethylase that specifically demethylates 'Lys-36' of histone H3, thereby playing a central role in histone code. Preferentially demethylates dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36'. May also recognize and bind to some phosphorylated proteins and promote their ubiquitination and degradation. Required to maintain the heterochromatic state. Associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Required to sustain centromeric integrity and genomic stability, particularly during mitosis. Regulates circadian gene expression by repressing the transcriptional activator activity of CLOCK-BMAL1 heterodimer and RORA in a catalytically-independent manner.
• Tissue Specificity: Widely expressed, with highest levels in brain, testis and ovary, followed by lung.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:HS10620-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 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 Lysine-specific demethylase 2A (KDM2A).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lysine-specific demethylase 2A (KDM2A).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Lysine-specific demethylase 2A (KDM2A).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Lysine-specific demethylase 2A (KDM2A).	[11]

9 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 Lysine-specific demethylase 2A (KDM2A).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysine-specific demethylase 2A (KDM2A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific demethylase 2A (KDM2A).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lysine-specific demethylase 2A (KDM2A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lysine-specific demethylase 2A (KDM2A).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Lysine-specific demethylase 2A (KDM2A).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Lysine-specific demethylase 2A (KDM2A).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysine-specific demethylase 2A (KDM2A).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lysine-specific demethylase 2A (KDM2A).	[12]

References

• [1] 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.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] 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.
• [12] KDM2A interacts with estrogen receptor to promote bisphenol A and S-induced breast cancer cell proliferation by repressing TET2 expression. Ecotoxicol Environ Saf. 2023 Jun 12;262:115132. doi: 10.1016/j.ecoenv.2023.115132. Online ahead of print.