Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILR7E4)

• DOT Name: Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6)
• Synonyms: EC 1.14.11.-; Histone arginine demethylase JMJD6; JmjC domain-containing protein 6; Jumonji domain-containing protein 6; Lysyl-hydroxylase JMJD6; Peptide-lysine 5-dioxygenase JMJD6; Phosphatidylserine receptor; Protein PTDSR
• Gene Name: JMJD6
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Bronchiectasis
  Choriocarcinoma
  Colon carcinoma
  Cystic fibrosis
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Glioma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Melanoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Periodontal disease
  Uveal Melanoma
  Von hippel-lindau disease
  Adult glioblastoma
  Colon cancer
  Cutaneous melanoma
  Gingivitis
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Mesothelioma
  Neoplasm
  Neuralgia
  Periodontitis
  Prostate cancer
  Prostate neoplasm
  Breast neoplasm
  Chronic hepatitis B virus infection
  Hepatitis B virus infection
  Neuroblastoma
  Triple negative breast cancer
• UniProt ID: JMJD6_HUMAN
• PDB ID: 3K2O; 3LD8; 3LDB; 6BNH; 6GDY; 6MEV
• EC Number: 1.14.11.-
• Pfam ID: PF02373
• Sequence:
  MNHKSKKRIREAKRSARPELKDSLDWTRHNYYESFSLSPAAVADNVERADALQLSVEEFV
  ERYERPYKPVVLLNAQEGWSAQEKWTLERLKRKYRNQKFKCGEDNDGYSVKMKMKYYIEY
  MESTRDDSPLYIFDSSYGEHPKRRKLLEDYKVPKFFTDDLFQYAGEKRRPPYRWFVMGPP
  RSGTGIHIDPLGTSAWNALVQGHKRWCLFPTSTPRELIKVTRDEGGNQQDEAITWFNVIY
  PRTQLPTWPPEFKPLEILQKPGETVFVPGGWWHVVLNLDTTIAITQNFASSTNFPVVWHK
  TVRGRPKLSRKWYRILKQEHPELAVLADSVDLQESTGIASDSSSDSSSSSSSSSSDSDSE
  CESGSEGDGTVHRRKKRRTCSMVGNGDTTSQDDCVSKERSSSR
• Function: Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase. Acts as a lysyl-hydroxylase that catalyzes 5-hydroxylation on specific lysine residues of target proteins such as U2AF2/U2AF65 and LUC7L2. Regulates RNA splicing by mediating 5-hydroxylation of U2AF2/U2AF65, affecting the pre-mRNA splicing activity of U2AF2/U2AF65. Hydroxylates its own N-terminus, which is required for homooligomerization. Plays a role in the regulation of nucleolar liquid-liquid phase separation (LLPS) by post-translationally modifying LIAT1 at its lysine-rich domain which inhibits LIAT1 nucleolar targeting. In addition to peptidyl-lysine 5-dioxygenase activity, may act as an RNA hydroxylase, as suggested by its ability to bind single strand RNA. Also acts as an arginine demethylase which preferentially demethylates asymmetric dimethylation. Demethylates histone H3 at 'Arg-2' (H3R2me) and histone H4 at 'Arg-3' (H4R3me), including mono-, symmetric di- and asymmetric dimethylated forms, thereby playing a role in histone code. However, histone arginine demethylation may not constitute the primary activity in vivo. In collaboration with BRD4, interacts with the positive transcription elongation factor b (P-TEFb) complex in its active form to regulate polymerase II promoter-proximal pause release for transcriptional activation of a large cohort of genes. On distal enhancers, so called anti-pause enhancers, demethylates both histone H4R3me2 and the methyl cap of 7SKsnRNA leading to the dismissal of the 7SKsnRNA:HEXIM1 inhibitor complex. After removal of repressive marks, the complex BRD4:JMJD6 attract and retain the P-TEFb complex on chromatin, leading to its activation, promoter-proximal polymerase II pause release, and transcriptional activation. Demethylates other arginine methylated-proteins such as ESR1. Has no histone lysine demethylase activity. Required for differentiation of multiple organs during embryogenesis. Acts as a key regulator of hematopoietic differentiation: required for angiogenic sprouting by regulating the pre-mRNA splicing activity of U2AF2/U2AF65. Seems to be necessary for the regulation of macrophage cytokine responses.
• Tissue Specificity: Highly expressed in the heart, skeletal muscle and kidney. Expressed at moderate or low level in brain, placenta, lung, liver, pancreas, spleen, thymus, prostate, testis and ovary. Up-regulated in many patients with chronic pancreatitis. Expressed in nursing thymic epithelial cells.
• Reactome Pathway:
  Protein hydroxylation (R-HSA-9629569)
  HDMs demethylate histones (R-HSA-3214842)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Bronchiectasis	DIS5MYEE	Strong	Altered Expression	[5]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	Strong	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[8]
Periodontal disease	DISJQHVN	Strong	Genetic Variation	[14]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[15]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Altered Expression	[6]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[16]
Colon cancer	DISVC52G	moderate	Biomarker	[7]
Cutaneous melanoma	DIS3MMH9	moderate	Biomarker	[12]
Gingivitis	DISC8RMX	moderate	Biomarker	[17]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[16]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[18]
Mesothelioma	DISKWK9M	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Neuralgia	DISWO58J	moderate	Biomarker	[19]
Periodontitis	DISI9JOI	moderate	Biomarker	[17]
Prostate cancer	DISF190Y	moderate	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	moderate	Biomarker	[12]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[20]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Altered Expression	[21]
Hepatitis B virus infection	DISLQ2XY	Limited	Biomarker	[21]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[22]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[26]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[28]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[29]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[35]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[36]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[37]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[33]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 (JMJD6).	[38]

References

• [1] JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation.PLoS Biol. 2014 Mar 25;12(3):e1001819. doi: 10.1371/journal.pbio.1001819. eCollection 2014 Mar.
• [2] Inhibition of JMJD6 expression reduces the proliferation, migration and invasion of neuroglioma stem cells.Neoplasma. 2017;64(5):700-708. doi: 10.4149/neo_2017_507.
• [3] Thymic epithelial cell-specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes.Biochem Biophys Res Commun. 2017 Jul 15;489(1):8-13. doi: 10.1016/j.bbrc.2017.05.113. Epub 2017 May 22.
• [4] JMJD6 regulates histone H2A.X phosphorylation and promotes autophagy in triple-negative breast cancer cells via a novel tyrosine kinase activity.Oncogene. 2019 Feb;38(7):980-997. doi: 10.1038/s41388-018-0466-y. Epub 2018 Sep 5.
• [5] Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis.J Clin Invest. 2002 Mar;109(5):661-70. doi: 10.1172/JCI13572.
• [6] Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta.Endocrinology. 2015 Aug;156(8):3012-25. doi: 10.1210/en.2015-1262. Epub 2015 Jun 2.
• [7] Livin promotes colon cancer progression by regulation of H2A.X(Y39ph) via JMJD6.Life Sci. 2019 Oct 1;234:116788. doi: 10.1016/j.lfs.2019.116788. Epub 2019 Aug 22.
• [8] Jumonji domain-containing 6 (JMJD6) identified as a potential therapeutic target in ovarian cancer.Signal Transduct Target Ther. 2019 Jul 26;4:24. doi: 10.1038/s41392-019-0055-8. eCollection 2019.
• [9] The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis.Clin Epigenetics. 2016 Apr 14;8:38. doi: 10.1186/s13148-016-0205-6. eCollection 2016.
• [10] JMJD6 promotes hepatocellular carcinoma carcinogenesis by targeting CDK4.Int J Cancer. 2019 May 15;144(10):2489-2500. doi: 10.1002/ijc.31816. Epub 2018 Oct 31.
• [11] PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6.Nucleic Acids Res. 2016 Dec 15;44(22):10662-10675. doi: 10.1093/nar/gkw808. Epub 2016 Sep 8.
• [12] Ras-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression.Front Genet. 2018 Dec 18;9:675. doi: 10.3389/fgene.2018.00675. eCollection 2018.
• [13] MiR-770 inhibits tumorigenesis and EMT by targeting JMJD6 and regulating WNT/-catenin pathway in non-small cell lung cancer.Life Sci. 2017 Nov 1;188:163-171. doi: 10.1016/j.lfs.2017.09.002. Epub 2017 Sep 4.
• [14] Effects of smoking and genotype on the PSR index of periodontal disease in adults aged 18-49.Int J Environ Res Public Health. 2012 Aug;9(8):2839-50. doi: 10.3390/ijerph9082839. Epub 2012 Aug 10.
• [15] KRas-ERK signalling promotes the onset and maintenance of uveal melanoma through regulating JMJD6-mediated H2A.X phosphorylation at tyrosine 39.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):4257-4265. doi: 10.1080/21691401.2019.1673764.
• [16] Transcription elongation factors represent in vivo cancer dependencies in glioblastoma.Nature. 2017 Jul 20;547(7663):355-359. doi: 10.1038/nature23000. Epub 2017 Jul 5.
• [17] Clinical periodontal and microbiologic parameters in patients with rheumatoid arthritis.J Periodontol. 2011 Oct;82(10):1424-32. doi: 10.1902/jop.2011.100481. Epub 2011 Mar 15.
• [18] Jumonji domain-containing protein 6 functions as a marker of head and neck squamous cell carcinoma at advanced stage with no effect on prognosis.Oncol Lett. 2019 Dec;18(6):5843-5852. doi: 10.3892/ol.2019.10938. Epub 2019 Sep 30.
• [19] JMJD6 exerts function in neuropathic pain by regulating NFB following peripheral nerve injury in rats.Int J Mol Med. 2018 Jul;42(1):633-642. doi: 10.3892/ijmm.2018.3613. Epub 2018 Apr 3.
• [20] JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter.Biochem J. 2018 Jan 15;475(1):355-371. doi: 10.1042/BCJ20170664.
• [21] Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection.Sci Rep. 2014 Sep 15;4:6359. doi: 10.1038/srep06359.
• [22] JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma.Nat Commun. 2019 Jul 25;10(1):3319. doi: 10.1038/s41467-019-11132-w.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] 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.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [28] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [29] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [30] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [31] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [32] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [33] 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.
• [34] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [37] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [38] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [39] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.