Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCN5ST8)

• DOT Name: Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8)
• Synonyms: EC 1.14.11.73; EC 3.4.-.-; JmjC domain-containing protein 5; Jumonji C domain-containing protein 5; L-arginine (3R)-hydroxylase KDM8
• Gene Name: KDM8
• Related Disease:
  Advanced cancer
  Breast adenocarcinoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
  Breast cancer
  Breast carcinoma
  Squamous cell carcinoma
• UniProt ID: KDM8_HUMAN
• PDB ID: 3UYJ; 4AAP; 4GAZ; 4GJY; 4GJZ; 4QU1; 5FBJ; 6AVS; 6AX3; 6F4M; 6F4N; 6F4O; 6F4P; 6F4Q; 6F4R; 6F4S; 6F4T; 6I9L; 6I9M; 6I9N; 7DYT; 7DYU; 7DYV; 7DYW; 7DYX; 7UQ3
• EC Number: 1.14.11.73; 3.4.-.-
• Pfam ID: PF13621
• Sequence:
  MAGDTHCPAEPLAREGTLWEALRALLPHSKEDLKLDLGEKVERSVVTLLQRATELFYEGR
  RDECLQSSEVILDYSWEKLNTGTWQDVDKDWRRVYAIGCLLKALCLCQAPEDANTVAAAL
  RVCDMGLLMGAAILGDILLKVAAILQTHLPGKRPARGSLPEQPCTKKARADHGLIPDVKL
  EKTVPRLHRPSLQHFREQFLVPGRPVILKGVADHWPCMQKWSLEYIQEIAGCRTVPVEVG
  SRYTDEEWSQTLMTVNEFISKYIVNEPRDVGYLAQHQLFDQIPELKQDISIPDYCSLGDG
  EEEEITINAWFGPQGTISPLHQDPQQNFLVQVMGRKYIRLYSPQESGALYPHDTHLLHNT
  SQVDVENPDLEKFPKFAKAPFLSCILSPGEILFIPVKYWHYVRALDLSFSVSFWWS
• Function: Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase. Endopeptidase that cleaves histones N-terminal tails at the carboxyl side of methylated arginine or lysine residues, to generate 'tailless nucleosomes', which may trigger transcription elongation. Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, continues to digest histones tails via its aminopeptidase activity. Upon DNA damage, cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated 'Lys-9' (H3K9me1). The histone variant H3F3A is the major target for cleavage. Additionally, acts as a Fe(2+) and 2-oxoglutarate-dependent monooxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of 'Arg-137' of RPS6 and 'Arg-141' of RCCD1, but the biological significance of this activity remains to be established. Regulates mitosis through different mechanisms: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, is involved in proper mitotic spindle organization and chromosome segregation. Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition. Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation. Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition. Regulates the circadian gene expression in the liver. Represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer in a catalytically-independent manner. Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation.
• Tissue Specificity: Weakly expressed in most cells. Highly expressed in breast cancer cells . Expressed in embryonic stem cells .
• Reactome Pathway: Protein hydroxylation (R-HSA-9629569)
• BioCyc Pathway: MetaCyc:ENSG00000155666-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
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast adenocarcinoma	DISMPHJ0	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[6]

1 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 Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the localization of Bifunctional peptidase and arginyl-hydroxylase JMJD5 (KDM8).	[10]

References

• [1] Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5.J Cancer Res Ther. 2018 Sep;14(Supplement):S609-S615. doi: 10.4103/0973-1482.187292.
• [2] Overexpression of histone demethylase JMJD5 promotes metastasis and indicates a poor prognosis in breast cancer.Int J Clin Exp Pathol. 2015 Sep 1;8(9):10325-34. eCollection 2015.
• [3] Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome.Mol Cancer Ther. 2017 Feb;16(2):397-407. doi: 10.1158/1535-7163.MCT-16-0588. Epub 2016 Dec 15.
• [4] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [5] KDM8/JMJD5 as a dual coactivator of AR and PKM2 integrates AR/EZH2 network and tumor metabolism in CRPC.Oncogene. 2019 Jan;38(1):17-32. doi: 10.1038/s41388-018-0414-x. Epub 2018 Aug 2.
• [6] Down-regulation of JMJD5 suppresses metastasis and induces apoptosis in oral squamous cell carcinoma by regulating p53/NF-B pathway.Biomed Pharmacother. 2019 Jan;109:1994-2004. doi: 10.1016/j.biopha.2018.07.144. Epub 2018 Nov 26.
• [7] 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.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] JMJD5 interacts with p53 and negatively regulates p53 function in control of cell cycle and proliferation. Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2286-95. doi: 10.1016/j.bbamcr.2015.05.026. Epub 2015 May 27.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.