Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN6KAE6)

• DOT Name: Lysine-specific demethylase 4D (KDM4D)
• Synonyms: EC 1.14.11.66; JmjC domain-containing histone demethylation protein 3D; Jumonji domain-containing protein 2D; -trimethyl-L-lysine(9) demethylase 4D
• Gene Name: KDM4D
• Related Disease:
  Adenocarcinoma
  Bone osteosarcoma
  Colorectal carcinoma
  Colorectal neoplasm
  Gastrointestinal stromal tumour
  Metastatic malignant neoplasm
  Osteosarcoma
  Pancreatic adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Advanced cancer
  Neoplasm
• UniProt ID: KDM4D_HUMAN
• PDB ID: 3DXT ; 3DXU ; 4D6Q ; 4D6R ; 4D6S ; 4HON ; 4HOO ; 5F5A ; 5F5C ; 5FP4 ; 5FP7 ; 5FP8 ; 5FP9 ; 5FPA ; 5FPB ; 5PH0 ; 5PH1 ; 5PH2 ; 5PH3 ; 5PH4 ; 5PH5 ; 5PH6 ; 5PH7 ; 5PH8 ; 5PH9 ; 5PHA ; 5PHB ; 5PHC ; 5PHD ; 5PHE ; 5PHF ; 5PHG ; 5PHH ; 5PHI ; 5PHJ ; 5PHK ; 5PHL ; 5PHM ; 5PHN ; 5PHO ; 5PHP ; 5PHQ ; 5PHR ; 5PHS ; 5PHT ; 5PHU ; 5PHV ; 5PHW ; 5PHX ; 5PHY ; 5PHZ ; 5PI0 ; 5PI1 ; 5PI2 ; 5PI3 ; 5PI4 ; 5PI5 ; 5PI6 ; 5PI7 ; 5PI8 ; 5PI9 ; 5PIA ; 5PIB ; 5PIC ; 5PID ; 5PIE ; 5PIF ; 5PIG ; 5PIH ; 5PII ; 5PIJ ; 5PIK ; 5PIL ; 5PIM ; 5PIN ; 5PIO ; 5PIP ; 5PIQ ; 5PIR ; 5PIS ; 5PIT ; 5PIU ; 5PIV ; 5PIW ; 5PIX ; 5PIY ; 5PIZ ; 5PJ0 ; 5PJ1 ; 5PJ2 ; 5PJ3 ; 5PJ4 ; 5PJ5 ; 5PJ6 ; 5PJ7 ; 5PJ8 ; 5PJ9 ; 5PJA ; 5PJB ; 5PJC ; 5PJD ; 5PJE ; 5PJF ; 5PJG ; 5PJH ; 5PJI ; 5PJJ ; 5PJK ; 5PJL ; 5PJM ; 5PJN ; 5PJO ; 5PJP ; 5PJQ ; 5PJR ; 5PJS ; 5PJT ; 5PJU ; 5PJV ; 5PJW ; 5PJX ; 5PJY ; 5PJZ ; 5PK0 ; 5PK1 ; 5PK2 ; 5PK3 ; 5PK4 ; 5PK5 ; 5PK6 ; 5PK7 ; 5PK8 ; 5PK9 ; 5PKA ; 5PKB ; 5PKC ; 5PKD ; 5PKE ; 5PKF ; 5PKG ; 5PKH ; 5PKI ; 5PKJ ; 5PKK ; 5PKL ; 5PKM ; 5PKN ; 5PKO ; 5PKP ; 5PKQ ; 5PKR ; 5PKS ; 5PKT ; 5PKU ; 5PKV ; 5PKW ; 5PKX ; 5PKY ; 5PKZ ; 5PL0 ; 5PL1 ; 5PL2 ; 5PL3 ; 5PL4 ; 5PL5 ; 5PL6 ; 5PL7 ; 5PL8 ; 5PL9 ; 5PLA ; 5PLB ; 5PLC ; 5PLD ; 5PLE ; 5PLF ; 5PLG ; 5PLH ; 5PLI ; 5PLJ ; 5PLK ; 5PLL ; 5PLM ; 5PLN ; 5PLO ; 5PLP ; 5PLQ ; 5PLR ; 5PLS ; 5PLT ; 5PLU ; 5PLV ; 5PLW ; 5PLX ; 5PLY ; 5PLZ ; 5PM0 ; 5PM1 ; 5PM2 ; 5PM3 ; 5PM4 ; 5PM5 ; 5PM6 ; 5PM7 ; 5PM8 ; 5PM9 ; 5PMA ; 5PMB ; 5PMC ; 5PMD ; 5PME ; 5PMF ; 5PMG ; 5PMH ; 5PMI ; 5PMJ ; 5PMK ; 5PML ; 5PMM ; 5PMN ; 5PMO ; 5PMP ; 5PMQ ; 5PMR ; 5PMS ; 5PMT ; 5PMU ; 5PMV ; 5PMW ; 5PMX ; 5PMY ; 5PMZ ; 5PN0 ; 5PN1 ; 5PN2 ; 5PN3 ; 5PN4 ; 5PN5 ; 5PN6 ; 5PN7 ; 5PN8 ; 5PN9 ; 5PNA ; 5PNB ; 5PNC ; 5PND ; 5PNE ; 5PNF ; 5PNG ; 5PNH ; 5PNI ; 5PNJ ; 5PNK ; 5PNL ; 5PNM ; 5PNN ; 5PNO ; 5PNP ; 5PNQ ; 5PNR ; 5PNS ; 5PNU ; 5PNV ; 5PNW ; 6ETE ; 6ETG ; 6ETS ; 6ETT ; 6ETU ; 6ETV ; 6ETW ; 6F5Q ; 6F5R ; 6F5S ; 6F5T ; 6H0W ; 6H0X ; 6H0Y ; 6H0Z ; 6H10 ; 6H11 ; 7DYG ; 7DYQ ; 8WUG
• EC Number: 1.14.11.66
• Pfam ID: PF02373 ; PF02375
• Sequence:
  METMKSKANCAQNPNCNIMIFHPTKEEFNDFDKYIAYMESQGAHRAGLAKIIPPKEWKAR
  ETYDNISEILIATPLQQVASGRAGVFTQYHKKKKAMTVGEYRHLANSKKYQTPPHQNFED
  LERKYWKNRIYNSPIYGADISGSLFDENTKQWNLGHLGTIQDLLEKECGVVIEGVNTPYL
  YFGMWKTTFAWHTEDMDLYSINYLHLGEPKTWYVVPPEHGQRLERLARELFPGSSRGCGA
  FLRHKVALISPTVLKENGIPFNRITQEAGEFMVTFPYGYHAGFNHGFNCAEAINFATPRW
  IDYGKMASQCSCGEARVTFSMDAFVRILQPERYDLWKRGQDRAVVDHMEPRVPASQELST
  QKEVQLPRRAALGLRQLPSHWARHSPWPMAARSGTRCHTLVCSSLPRRSAVSGTATQPRA
  AAVHSSKKPSSTPSSTPGPSAQIIHPSNGRRGRGRPPQKLRAQELTLQTPAKRPLLAGTT
  CTASGPEPEPLPEDGALMDKPVPLSPGLQHPVKASGCSWAPVP
• Function: Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.
• Reactome Pathway: HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:MONOMER66-43295

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[3]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[3]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lysine-specific demethylase 4D (KDM4D).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysine-specific demethylase 4D (KDM4D).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Lysine-specific demethylase 4D (KDM4D).	[8]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Lysine-specific demethylase 4D (KDM4D).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysine-specific demethylase 4D (KDM4D).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysine-specific demethylase 4D (KDM4D).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lysine-specific demethylase 4D (KDM4D).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Lysine-specific demethylase 4D (KDM4D).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Lysine-specific demethylase 4D (KDM4D).	[14]

References

• [1] KDM4D Predicts Recurrence in Exocrine Pancreatic Cells of Resection Margins from Patients with Pancreatic Adenocarcinoma.Anticancer Res. 2018 Apr;38(4):2295-2302. doi: 10.21873/anticanres.12474.
• [2] Regulation of tumor suppressor p53 and HCT116 cell physiology by histone demethylase JMJD2D/KDM4D.PLoS One. 2012;7(4):e34618. doi: 10.1371/journal.pone.0034618. Epub 2012 Apr 13.
• [3] Histone Demethylase JMJD2D Interacts With -Catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice.Gastroenterology. 2019 Mar;156(4):1112-1126. doi: 10.1053/j.gastro.2018.11.036. Epub 2018 Nov 23.
• [4] Correction to: Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1/VEGFA signalling.Mol Cancer. 2018 Sep 13;17(1):135. doi: 10.1186/s12943-018-0885-y.
• [5] Cooperation between ETS variant 2 and Jumonji domaincontaining 2 histone demethylases.Mol Med Rep. 2018 Apr;17(4):5518-5527. doi: 10.3892/mmr.2018.8507. Epub 2018 Jan 26.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] 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.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.