Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDN3EGK)

• DOT Name: Lysine-specific demethylase 4A (KDM4A)
• Synonyms: EC 1.14.11.66; EC 1.14.11.69; JmjC domain-containing histone demethylation protein 3A; Jumonji domain-containing protein 2A; -trimethyl-L-lysine(36) demethylase 4A; -trimethyl-L-lysine(9) demethylase 4A
• Gene Name: KDM4A
• UniProt ID: KDM4A_HUMAN
• PDB ID: 2GF7 ; 2GFA ; 2GP3 ; 2GP5 ; 2OQ6 ; 2OQ7 ; 2OS2 ; 2OT7 ; 2OX0 ; 2P5B ; 2PXJ ; 2Q8C ; 2Q8D ; 2Q8E ; 2QQR ; 2QQS ; 2VD7 ; 2WWJ ; 2YBK ; 2YBP ; 2YBS ; 3NJY ; 3PDQ ; 3RVH ; 3U4S ; 4AI9 ; 4BIS ; 4GD4 ; 4URA ; 4V2V ; 4V2W ; 5A7N ; 5A7O ; 5A7P ; 5A7Q ; 5A7S ; 5A7W ; 5A80 ; 5ANQ ; 5D6W ; 5D6X ; 5D6Y ; 5F2S ; 5F2W ; 5F32 ; 5F37 ; 5F39 ; 5F3C ; 5F3E ; 5F3G ; 5F3I ; 5F5I ; 5FPV ; 5FWE ; 5FY8 ; 5FYC ; 5FYH ; 5FYI ; 5LY1 ; 5LY2 ; 5TVR ; 5TVS ; 5VAR ; 5VGI ; 5VMP ; 6CG1 ; 6CG2 ; 6G5W ; 6G5X ; 6H4O ; 6H4P ; 6H4Q ; 6H4R ; 6H4S ; 6H4T ; 6H4U ; 6H4V ; 6H4W ; 6H4X ; 6H4Y ; 6H8P ; 6HGT ; 7D4A ; 7EQV ; 8WD3
• EC Number: 1.14.11.66; 1.14.11.69
• Pfam ID: PF02373 ; PF02375 ; PF13831 ; PF18104 ; PF13832
• Sequence:
  MASESETLNPSARIMTFYPTMEEFRNFSRYIAYIESQGAHRAGLAKVVPPKEWKPRASYD
  DIDDLVIPAPIQQLVTGQSGLFTQYNIQKKAMTVREFRKIANSDKYCTPRYSEFEELERK
  YWKNLTFNPPIYGADVNGTLYEKHVDEWNIGRLRTILDLVEKESGITIEGVNTPYLYFGM
  WKTSFAWHTEDMDLYSINYLHFGEPKSWYSVPPEHGKRLERLAKGFFPGSAQSCEAFLRH
  KMTLISPLMLKKYGIPFDKVTQEAGEFMITFPYGYHAGFNHGFNCAESTNFATRRWIEYG
  KQAVLCSCRKDMVKISMDVFVRKFQPERYKLWKAGKDNTVIDHTLPTPEAAEFLKESELP
  PRAGNEEECPEEDMEGVEDGEEGDLKTSLAKHRIGTKRHRVCLEIPQEVSQSELFPKEDL
  SSEQYEMTECPAALAPVRPTHSSVRQVEDGLTFPDYSDSTEVKFEELKNVKLEEEDEEEE
  QAAAALDLSVNPASVGGRLVFSGSKKKSSSSLGSGSSRDSISSDSETSEPLSCRAQGQTG
  VLTVHSYAKGDGRVTVGEPCTRKKGSAARSFSERELAEVADEYMFSLEENKKSKGRRQPL
  SKLPRHHPLVLQECVSDDETSEQLTPEEEAEETEAWAKPLSQLWQNRPPNFEAEKEFNET
  MAQQAPHCAVCMIFQTYHQVEFGGFNQNCGNASDLAPQKQRTKPLIPEMCFTSTGCSTDI
  NLSTPYLEEDGTSILVSCKKCSVRVHASCYGVPPAKASEDWMCSRCSANALEEDCCLCSL
  RGGALQRANDDRWVHVSCAVAILEARFVNIAERSPVDVSKIPLPRFKLKCIFCKKRRKRT
  AGCCVQCSHGRCPTAFHVSCAQAAGVMMQPDDWPFVVFITCFRHKIPNLERAKGALQSIT
  AGQKVISKHKNGRFYQCEVVRLTTETFYEVNFDDGSFSDNLYPEDIVSQDCLQFGPPAEG
  EVVQVRWTDGQVYGAKFVASHPIQMYQVEFEDGSQLVVKRDDVYTLDEELPKRVKSRLSV
  ASDMRFNEIFTEKEVKQEKKRQRVINSRYREDYIEPALYRAIME
• Function: Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively; [Isoform 2]: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000066135-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 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 Lysine-specific demethylase 4A (KDM4A).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Lysine-specific demethylase 4A (KDM4A).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lysine-specific demethylase 4A (KDM4A).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lysine-specific demethylase 4A (KDM4A).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Lysine-specific demethylase 4A (KDM4A).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lysine-specific demethylase 4A (KDM4A).	[6]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Lysine-specific demethylase 4A (KDM4A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysine-specific demethylase 4A (KDM4A).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Lysine-specific demethylase 4A (KDM4A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lysine-specific demethylase 4A (KDM4A).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Lysine-specific demethylase 4A (KDM4A).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysine-specific demethylase 4A (KDM4A).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lysine-specific demethylase 4A (KDM4A).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysine-specific demethylase 4A (KDM4A).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Lysine-specific demethylase 4A (KDM4A).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Lysine-specific demethylase 4A (KDM4A).	[15]

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] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] 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.
• [6] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [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] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [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] Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein. J Biol Chem. 2005 Aug 5;280(31):28507-18. doi: 10.1074/jbc.M413687200. Epub 2005 May 31.