Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEKG0KD)

• DOT Name: Lysine-specific demethylase 5D (KDM5D)
• Synonyms: EC 1.14.11.67; Histocompatibility Y antigen; H-Y; Histone demethylase JARID1D; Jumonji/ARID domain-containing protein 1D; Protein SmcY; -trimethyl-L-lysine(4) demethylase 5D
• Gene Name: KDM5D
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Clear cell renal carcinoma
  Coronary heart disease
  Fatty liver disease
  Huntington disease
  Knee osteoarthritis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Cardiovascular disease
  Graft-versus-host disease
  Gastric cancer
  Neoplasm
  Stomach cancer
  Tuberculosis
• UniProt ID: KDM5D_HUMAN
• PDB ID: 2E6R; 2YQE
• EC Number: 1.14.11.67
• Pfam ID: PF01388 ; PF02373 ; PF02375 ; PF21323 ; PF00628 ; PF08429 ; PF02928
• Sequence:
  MEPGCDEFLPPPECPVFEPSWAEFQDPLGYIAKIRPIAEKSGICKIRPPADWQPPFAVEV
  DNFRFTPRVQRLNELEAQTRVKLNYLDQIAKFWEIQGSSLKIPNVERKILDLYSLSKIVI
  EEGGYEAICKDRRWARVAQRLHYPPGKNIGSLLRSHYERIIYPYEMFQSGANHVQCNTHP
  FDNEVKDKEYKPHSIPLRQSVQPSKFSSYSRRAKRLQPDPEPTEEDIEKHPELKKLQIYG
  PGPKMMGLGLMAKDKDKTVHKKVTCPPTVTVKDEQSGGGNVSSTLLKQHLSLEPCTKTTM
  QLRKNHSSAQFIDSYICQVCSRGDEDDKLLFCDGCDDNYHIFCLLPPLPEIPRGIWRCPK
  CILAECKQPPEAFGFEQATQEYSLQSFGEMADSFKSDYFNMPVHMVPTELVEKEFWRLVS
  SIEEDVTVEYGADIHSKEFGSGFPVSNSKQNLSPEEKEYATSGWNLNVMPVLDQSVLCHI
  NADISGMKVPWLYVGMVFSAFCWHIEDHWSYSINYLHWGEPKTWYGVPSLAAEHLEEVMK
  MLTPELFDSQPDLLHQLVTLMNPNTLMSHGVPVVRTNQCAGEFVITFPRAYHSGFNQGYN
  FAEAVNFCTADWLPAGRQCIEHYRRLRRYCVFSHEELICKMAAFPETLDLNLAVAVHKEM
  FIMVQEERRLRKALLEKGVTEAEREAFELLPDDERQCIKCKTTCFLSALACYDCPDGLVC
  LSHINDLCKCSSSRQYLRYRYTLDELPTMLHKLKIRAESFDTWANKVRVALEVEDGRKRS
  FEELRALESEARERRFPNSELLQRLKNCLSEVEACIAQVLGLVSGQVARMDTPQLTLTEL
  RVLLEQMGSLPCAMHQIGDVKDVLEQVEAYQAEAREALATLPSSPGLLRSLLERGQQLGV
  EVPEAHQLQQQVEQAQWLDEVKQALAPSAHRGSLVIMQGLLVMGAKIASSPSVDKARAEL
  QELLTIAERWEEKAHFCLEARQKHPPATLEAIIRETENIPVHLPNIQALKEALTKAQAWI
  ADVDEIQNGDHYPCLDDLEGLVAVGRDLPVGLEELRQLELQVLTAHSWREKASKTFLKKN
  SCYTLLEVLCPCADAGSDSTKRSRWMEKALGLYQCDTELLGLSAQDLRDPGSVIVAFKEG
  EQKEKEGILQLRRTNSAKPSPLAPSLMASSPTSICVCGQVPAGVGVLQCDLCQDWFHGQC
  VSVPHLLTSPKPSLTSSPLLAWWEWDTKFLCPLCMRSRRPRLETILALLVALQRLPVRLP
  EGEALQCLTERAIGWQDRARKALASEDVTALLRQLAELRQQLQAKPRPEEASVYTSATAC
  DPIREGSGNNISKVQGLLENGDSVTSPENMAPGKGSDLELLSSLLPQLTGPVLELPEAIR
  APLEELMMEGDLLEVTLDENHSIWQLLQAGQPPDLDRIRTLLELEKFEHQGSRTRSRALE
  RRRRRQKVDQGRNVENLVQQELQSKRARSSGIMSQVGREEEHYQEKADRENMFLTPSTDH
  SPFLKGNQNSLQHKDSGSSAACPSLMPLLQLSYSDEQQL
• Function: Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. May play a role in spermatogenesis. Involved in transcriptional repression of diverse metastasis-associated genes; in this function seems to cooperate with ZMYND8. Suppresses prostate cancer cell invasion. Regulates androgen receptor (AR) transcriptional activity by demethylating H3K4me3 active transcription marks.
• Tissue Specificity: Expression is highly down-regulated in metastatic prostate tumors.
• Reactome Pathway: HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000012817-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Posttranslational Modification	[2]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[1]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[1]
Huntington disease	DISQPLA4	Strong	Altered Expression	[3]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	moderate	Altered Expression	[8]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Biomarker	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[10]
Stomach cancer	DISKIJSX	Limited	Biomarker	[10]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[11]

2 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 5D (KDM5D).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysine-specific demethylase 5D (KDM5D).	[13]

1 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 affects the methylation of Lysine-specific demethylase 5D (KDM5D).	[14]

References

• [1] A Novel Y-Specific Long Non-Coding RNA Associated with Cellular Lipid Accumulation in HepG2 cells and Atherosclerosis-related Genes.Sci Rep. 2017 Dec 1;7(1):16710. doi: 10.1038/s41598-017-17165-9.
• [2] Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma.Sci Rep. 2017 Mar 23;7:44876. doi: 10.1038/srep44876.
• [3] HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation.Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):E56-64. doi: 10.1073/pnas.1415195112. Epub 2014 Dec 22.
• [4] Comparison of Single Intra-Articular Injection of Novel Hyaluronan (HYA-JOINT Plus) with Synvisc-One for Knee Osteoarthritis: A Randomized, Controlled, Double-Blind Trial of Efficacy and Safety.J Bone Joint Surg Am. 2017 Mar 15;99(6):462-471. doi: 10.2106/JBJS.16.00469.
• [5] ATR inhibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D.J Clin Invest. 2018 Jul 2;128(7):2979-2995. doi: 10.1172/JCI96769. Epub 2018 Jun 4.
• [6] JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis.Cancer Res. 2016 Feb 15;76(4):831-43. doi: 10.1158/0008-5472.CAN-15-0906. Epub 2016 Jan 8.
• [7] A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR.PLoS One. 2011;6(6):e21699. doi: 10.1371/journal.pone.0021699. Epub 2011 Jun 28.
• [8] Proteomics based identification of KDM5 histone demethylases associated with cardiovascular disease.EBioMedicine. 2019 Mar;41:91-104. doi: 10.1016/j.ebiom.2019.02.040. Epub 2019 Feb 28.
• [9] Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission.Blood. 2005 Apr 1;105(7):2973-8. doi: 10.1182/blood-2004-09-3660. Epub 2004 Dec 21.
• [10] KDM5D inhibit epithelial-mesenchymal transition of gastric cancer through demethylation in the promoter of Cul4A in male.J Cell Biochem. 2019 Aug;120(8):12247-12258. doi: 10.1002/jcb.27308. Epub 2019 Mar 12.
• [11] Role played by human mannose-binding lectin polymorphisms in pulmonary tuberculosis.J Infect Dis. 2009 Mar 1;199(5):666-72. doi: 10.1086/596658.
• [12] 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.
• [13] 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.
• [14] 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.